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Leonard and Penny are returning from their first date (from the Season 1 finale The Tangerine Factor) while Howard and Raj spy on them using a webcam on the corridor. When Leonard suggests going over to Penny’s apartment, she tells him to "slow things down". The guys try to convince Leonard that the date did not go too well, which he denies. Later, Penny tells Sheldon that she lied to Leonard about graduating from community college as she feels that Leonard would not want to date a woman who is not smart and makes him promise not to tell Leonard. Unfortunately, Sheldon finds it difficult to keep the secret and moves out of the apartment as a result. He first stays in Raj’s apartment, but after he criticizes Aishwarya Rai (while comparing her to Madhuri Dixit), Raj leaves him with Howard. At Howard’s house, Sheldon is unable to sleep, so Howard gives him Valium and takes him back to the apartment. Sheldon, in his drugged state, tells Leonard the secret. The next morning, Leonard suggests Penny should join Pasadena City College, but tells her that he does not mind dating someone who isn’t smart after she asks, to which she slams her door in his face.

After the guys return from a Renaissance fair and see Penny with her new boyfriend, Eric, Leonard decides to once again pursue a relationship with Leslie. Thinking that she needs to "slow things down", Leslie agrees to date Leonard, repeatedly assuming the dominant role before conceding that Leonard should assume the "male role". With this new attitude, Leslie goes as far as evaluating Leonard’s genetic defects, and talking about procreating children with him. Sheldon explains to Penny that he feels uncomfortable with Leonard dating his arch enemy, who is a "sloppy, arrogant, sub-par scientist". After Penny’s advice, Sheldon formally approves the relationship between Leonard and Leslie. However, almost immediately, Leslie and Sheldon start an argument about the validity of loop quantum gravity, which Leslie supports, and string theory, which Sheldon supports. Leslie expects Leonard to back up her beliefs, but when Leonard prefers string theory, Leslie decides to dump him. Relieved, Sheldon tells Leonard to look on the bright side and that it is only another nine months until Comic Con.

Sheldon becomes distracted from playing Age of Conan by Penny who has been accidentally locked out of her apartment. Along with this event, Penny is frustrated by her failures in life such as not progressing in her acting career, and not having sex for six months. As Sheldon invites Penny into his apartment to wait for the locksmith to open her door, she becomes curious about the game Sheldon is playing, and quickly becomes addicted. In the following days, Penny experiences video game addiction, calls Sheldon at all times for help, and stops going to work to play the game nonstop. After talking with Leslie Winkle, Sheldon realizes that Penny needs to have sex to relieve her stress and regain her regular life. Sheldon then attempts to set Penny up with an online dating service, but fails miserably. In the end, Penny overcomes her addiction when she realizes she accepted to have a virtual date with Howard. Horrified, she promptly stops playing.

Raj is included in People magazine’s "30 Visionaries Under 30 Years Old to Watch" list for his discovery of the trans-Neptunian object 2008 NQ17, sparking jealousy from his friends. Despite Leonard’s comments that they need to be supportive, fame soon goes to Raj’s head: he receives star treatment from Dr. Gablehauser, gets an assistant, and even invites Penny to People’s reception. After the party, a very intoxicated Raj returns home with Penny, and via webcam introduces her to his parents as his girlfriend. The night ends with Penny denying being Raj’s girlfriend, and leaving after he becomes sick from over drinking. The following morning, a sober and shy Raj tries to apologize to Penny for his behavior. Although Raj attempts to leave a written note, Penny ultimately forces him to utter a barely audible "Sorry", at which point she forgives him.

Leonard is working nights on an experiment, resulting in his inability to drive Sheldon to the university. As a result, Sheldon must find another way to get to work. He asks Penny, Howard and Raj for assistance, but they all eject him from their respective vehicles for being annoying. The friends finally stage an "intervention" and tell Sheldon to get a driver’s license and learn to drive. After an eventful trip to the DMV, resulting in Sheldon getting his learner’s permit just to get him to leave, the group sets up a driving simulator for him in the living room. The ensuing practice shows that Sheldon is a horrible driver, but instead of admitting defeat, he simply concludes that he is too highly evolved to drive a car. In the end, Sheldon decides to live in his office at the university, so that he does not have to commute. However, Leonard reveals that he actually finished his experiment a week ago and is just enjoying the apartment without Sheldon.

After a lecture by Leonard and Sheldon, a graduate student named Ramona Nowitzki becomes obsessed with Sheldon, and insinuates herself into his life as a platonic girlfriend/assistant. Sheldon likes having someone who brings him free food and performs personal services for him. Ramona proves to be a helpful influence on Sheldon’s work, but he becomes tired of her as she prohibits his recreational activities, and forces him to solely concentrate on his research. Eventually Sheldon realizes that he is in "some sort of relationship" with Ramona, and seeks help from Penny and Leonard to get rid of her, without success. Things come to a conclusion when Sheldon reaches a breakthrough in his scientific research and Sheldon is extremely grateful and asks if he can do something for her. Ramona suggests they share credit for his discovery calling it "The Cooper-Nowitzki Theorem". Naturally, Sheldon refuses and subsequently kicks Ramona out. In the end, after reading a draft paper of the new theorem, another student approaches Sheldon in the same way Ramona did the first time.

When Penny’s cable gets cut, she comes over to the guys’ apartment to watch America’s Next Top Model. However, she accidentally sits on Sheldon’s spot on the couch and touches his onion rings, prompting Sheldon to banish her from his apartment. A series of confrontations between Sheldon and Penny follows, such as Sheldon cutting access to Penny’s Wi-fi and Penny ruining Sheldon’s laundry night. Eventually, Sheldon places Penny’s laundry on a telephone wire and dares her to get it. Leonard decides to end the confrontation between the two by asking Penny to complain to Sheldon’s mother (Sheldon’s kryptonite). Sheldon’s mother forces Sheldon to apologize to Penny and give back her laundry. Meanwhile, Howard finds out that the models in America’s Next Top Model are in a house in Los Angeles. Determined to get in the house, he and Raj search for the house using all available technology and they successfully manage to find it. The episode ends with Howard and Raj entering the house by posing as cable guys.

Howard meets Stephanie at a bar and invites her to drive the Mars rover at the Jet Propulsion Laboratory, but the plan fails when the rover winds up stuck in a Martian ditch. Subsequently, to hide evidence of what he did, Howard destroys all the security tapes and hard drives relating to the mission. Afterwards, Leonard has a hard time deciding how to tell Howard that he has started dating Stephanie. Leonard decides to go to Howard’s house to tell him personally, but while there, Stephanie calls Howard and gives him the news. Howard becomes very upset with Leonard, but this only lasts until Stephanie sets up Howard with another friend, and invites him on a double-date. In the end, Howard hears the news on TV that the rover found water on Mars in the bottom of the ditch, but as so much data was "inexplicably" lost no one will know who was responsible for the amazing discovery. The episode is titled for its minor sub-plot where Sheldon and Raj play a game of rock-paper-scissors-lizard-Spock, which is "The Lizard-Spock Expansion" of the traditional game of rock-paper-scissors. They play to decide who gets to watch what on TV, but they all choose Spock. They, along with Howard, play the game for the last dumpling. When they choose all Spock again, they play it where none of them may hold up Spock, but they choose all hold up Spock again anyways.

Sheldon considers Stephanie the only "tolerable" girlfriend that Leonard has had. As a result, Sheldon tries helping Leonard in his relationship with Stephanie, as otherwise he thinks Leonard will ruin it. However, Leonard does not want Sheldon’s help as he quickly becomes annoying, even joining the couple when they have a romantic dinner, and when they go to the movies. After believing that Leonard is losing Stephanie, Sheldon attempts to prove Leonard’s physical superiority to Stephanie by having him open a jar of white asparagus. However, Leonard shatters the jar by accident and has to get stitches. Following the trip to the hospital, Leonard finds Sheldon hacked his Facebook account, and changed his status to "In a relationship". Leonard worries that this will make him look desperate, but then finds that Stephanie changed her status to "Stephanie Barnett is in a relationship with Leonard Hofstadter". Sheldon then proclaims "Dr. Sheldon Cooper for the win."

For all practical purposes, Stephanie has moved into Leonard and Sheldon’s apartment, although Leonard does not acknowledge this. Meanwhile, Stephanie gives a physical examination to Sheldon, who complains about a ringing in his ear. After Penny shows up scantily clad in the guys’ apartment, it turns out that neither Leonard nor Sheldon ever told Stephanie about Penny. The morning does not go well following that; Penny proves to Leonard that Stephanie is living with him, and Stephanie buys Leonard new clothes that he ends up hating. Realizing that his relationship with Stephanie is moving too fast for him, Leonard tries to tell Stephanie to move out, but every time he tries she diverts him by initiating sex. Meanwhile, Sheldon sneaks into the hospital to test himself multiple times, as the ringing has not stopped. By the time Leonard gets back to the apartment, Stephanie has diagnosed Sheldon with a fake larynx inflammation, and instructs him not to speak at all. She calls the diagnosis a "Sheldonectomy".

Sheldon worries about the approaching Christmas holidays and his indecision about what gift to get Penny. After deciding on a basket of bath items, he discovers a wide selection available; unsure about what Penny is going to get him and what he should get her in return, he buys an entire array to cover all contingencies. Penny’s gift to Sheldon is a napkin both autographed and used by Leonard Nimoy. Sheldon is overwhelmed since he now possesses Nimoy’s DNA and can grow his own Leonard Nimoy. He responds by giving Penny all the gift baskets and then a rare "Sheldon" hug. Meanwhile, Leonard meets visiting researcher and fellow experimental physicist Dr. David Underhill. Although Leonard envies David for being handsome, charming, cool, and a more successful physicist than he is, he still jumps at David’s offer to help him in his research. However, Leonard’s joy of hanging out with David is hampered by jealousy when the latter meets Penny, and the two start dating. They later break up after she finds out he is married.

Howard designs a robot, M.O.N.T.E. (Mobile Omnidirectional Neutralization and Termination Eradicator) using which the guys plan to enter the "Southern California Robot Fighting League Round Robin Invitational". When Penny arrives at the apartment, Howard begins to flirt with her however this time he pushes her too far and she lashes out at him in anger, calling him ’pathetic and creepy’ and telling him he’ll die alone. A depressed Howard returns home and remains in his room, refusing to go to work. Leonard advises Penny to go to Howard’s house and apologize to him. When Penny goes to Howard’s home to apologize, he begins to tell her about all his failed romances. Penny consoles him by saying that he is a good guy at heart and that he just tries too hard to get girls. After this however, Howard tries to kiss Penny, which results in her punching him. Howard is left happy, feeling he is halfway to ’pity sex’. Meanwhile, the guys’ co-worker Barry Kripke also plans to enter his robot for the competition, and challenges Sheldon and the guys to a one-on-one fight using their robots. Sheldon accepts the challenge, but Kripke’s robot turns out to be far superior to M.O.N.T.E. and with Howard indisposed, Leonard and Raj plead with Sheldon to call off the fight, to no avail. During the fight, M.O.N.T.E. is destroyed by Kripke’s robot.

Sheldon hears that Kripke is in control of an Open Science Grid computer, so he plans to befriend him to get access to the computer. Socially inept, Sheldon has trouble understanding how to make a new friend, and his current friends are not of much help in this respect. During a trip to the bookstore, Sheldon tries making friends with a little girl while Leonard gets him to quickly exit before he is picked up as a pedophile. Sheldon uses a children’s book to help him design a flowchart to get new friends. This "scientific" procedure pays off, and Sheldon goes rock-climbing with Kripke which causes Sheldon to faint due to his fear of heights. Afterwards, they are back at the apartment, where Sheldon decides to cut off Raj as a friend to make room for Kripke. However, when Kripke reveals that he does not control use of the grid computer, Sheldon dismisses him and restores Raj’s place in the line-up.

Penny is experiencing financial difficulties, which may result in her finding a new place to live. Sheldon, after discussing her difficulties, does the logical thing and lends her some money out of his savings. This leads to an amusing role reversal: while Sheldon does not particularly care about when his loan is repaid, Penny begins displaying neurotic behavior, reacting irritably to anything that hints at her monetary troubles. After Leonard learns about Penny’s problems, he tries to help her cut expenses, and in the process also learns that her ex-boyfriend Kurt owes her $1800. Without telling Penny, Leonard and the guys go to Kurt’s place to collect the money, but they are unsuccessful (Kurt writes "I owe Penny $1800, Kurt" on Leonard’s forehead in indelible ink). Later, Penny pays Sheldon back, revealing that Kurt visited her the next morning and paid her in turn. However, much to Leonard’s disappointment, Kurt never told Penny about Leonard’s visit, and instead took the opportunity to get back together with her.

Leonard suddenly becomes worried when he learns his mother, accomplished psychiatrist and neuroscientist Dr. Beverly Hofstadter, is coming to visit. Upon arriving at the building, Beverly meets Penny, and by the time they reach Leonard’s apartment, Penny is in tears after having her childhood issues psychoanalyzed. Sheldon, on the other hand, instantly develops a comfortable relationship with Leonard’s mother, who turns out to be as strict and logical as himself. Howard and Raj also meet Beverly, but after learning that Howard still lives with his mother and that Raj cannot speak to women, she is quick to declare that they are in an "ersatz homosexual marriage". Later, Leonard goes to talk to Penny, and they both seek comfort in each other, discussing their respective childhood issues with their parents. As they become drunk, Penny and Leonard are about to have sex, but Leonard ruins the moment by using psychology and noting that he is having sex with his mom and she with her dad. Disgusted, Penny throws Leonard out of the apartment.

Penny accidentally shoots the paintball gun at Sheldon’s couch cushion, and she and Leonard have a hard time getting it cleaned. Naturally, Sheldon freaks out when he finds out his favorite spot has been damaged. In the end, Sheldon is still dissatisfied with the dry-cleaned cushion, and he team-kills Penny in the next paintball game, causing the others to "surrender, then (go to) Denny’s". Meanwhile, Leslie and Howard start sleeping together during a paintball match, and she is able to secure funds for his work, and even invites him to a trip to the CERN Large Hadron Collider project in Geneva. However, this turns out to be just Leslie’s way to control Howard. Although initially reluctant to be in this sort of relationship, Howard later happily accepts his role as a "sex toy/arm candy".

The guys take a train trip to a conference in San Francisco, where the guest speaker is 2006 Nobel Prize laureate Dr. George Smoot. However, the trip suddenly becomes more exciting when the guys realize Summer Glau of Terminator: The Sarah Connor Chronicles is on board. Leaving his shyness behind while drinking beer, Raj is the first to approach Summer, who gets along with him. Howard gets angry, but he notices that Raj drank non-alcoholic beer unbeknownst to him, causing a placebo effect. Howard notices this and gives Raj the bottle. Upon reading the label Raj reverts to his usual timid self. Howard then takes over, but creeps Summer out with his wild dreams and his awkward style. Leonard eventually gets his chance, but Summer gets off the train before he can introduce himself. Meanwhile, Sheldon realizes he forgot his USB flash drive with a paper he wants to show to Smoot, and he needs Penny to find it in his room and email the paper to him. In the end, Dr. Smoot (guest starring as himself) is not impressed with Sheldon’s proposal of research, asking him "With all due respect, Dr. Cooper, are you on crack?"

Penny develops home-made hair barrettes, called ’Penny Blossoms’, which she expects to turn into a profitable homebased business. Sheldon soon points out the flaws in her production process, and helps her develop a better assembly line. Leonard, Howard, and Raj also contribute their own ideas for efficiency, production and marketing. Leonard designs the sales website, and right away they get an order for a thousand Penny Blossoms from the East Rutherford, New Jersey Gay-Lesbian-Bisexual-Transgender Alliance. Despite their initial happiness, they realize Leonard included a one-day rush shipping option in the website, so the quintet has to work all night to fulfill the order. However, the next morning, they discover that the same group doubled their order, leading everyone to quit in exhaustion. Meanwhile, Sheldon (who had earlier drunk coffee to stay awake) races around the apartment dressed as The Flash.

The former tenants of the apartment above Leonard and Sheldon’s move out, and (after an unsuccessful attempt by Wolowitz to rent the apartment, by trying to leave his mother’s house) are replaced by an attractive blonde woman named Alicia, an aspiring actress who obtains a role as a dead hooker in an episode of the TV series CSI. The men become fascinated with Alicia, and she takes advantage of this by having them labor for her. As a result, Penny loses the guys’ attention, and also comes to resent the way Alicia exploits the men. She tries to gain her friends back by bribing them with Chinese food, offering to watch Battlestar Galactica, and even memorizing a quantum physics joke. After Alicia brags about her exploitation of the men, while also expressing derision of their incomes, Penny confronts her. Alicia responds by saying that Penny exploits the men in the same way that she herself does, which leads to a physical altercation. After the fight, the friends learn that Alicia is sleeping with one of the CSI producers, leading Penny to comment that Alicia is a "dead whore on TV, live one in real life".

When Penny accompanies the men to the comic book store to buy a present for her nephew’s birthday, the owner, Stuart, asks her out on a date, prompting jealousy in Leonard. To take his mind off the situtation, Leonard asks Howard and Raj to take him to a bar to socialize with women, but neither he nor Howard succeed in finding a woman to couple with. Stuart’s date with Penny goes well, but they are interrupted by Sheldon, who starts an argument with Stuart about who Bruce Wayne’s successor as Batman should be, during which Penny falls asleep.

Leslie ends her casual relationship with Howard, and he becomes depressed. Leonard and Raj decide to take him on a trip to Las Vegas, Nevada in order to cheer him up. While in Vegas, a prostitute named Mikayla approaches Raj, and eventually he and Leonard decide to hire her for Howard with her giving him the Jewish girlfriend role-playing treatment. Howard soon realizes she is a prostitute, but nevertheless he thanks Leonard and Raj for setting up this "date". Meanwhile, Sheldon, who has declined to go to Las Vegas, is delighted to spend the weekend alone, until he forgets his apartment key. He is then forced to spend the night at Penny’s apartment (like "an old married couple" per Penny) and, in the process, thinks he has a better understanding of the term "friends with benefits".

Howard celebrates the launch of his latest invention, a zero-gravity human-waste disposal system (a "space toilet"), to be used in the International Space Station, by buying all of his friends new comic books only for Howard to discover that he made a mistake that will cause the toilet to fail and explode after 10 flushes, and the guys convene to try and fix it (a la Apollo 13 ’s Ken Mattingly), working for a whole night to find a solution, even testing the toilet with meatloaf which Howard brought from his mother, saying: "It has been testing toilets for generations". In the end, the astronauts of the ISS report to NASA that they are going on an unscheduled "spacewalk", suggesting that Howard failed. While at the comic book store, Stuart tells Leonard that he is having a second date with Penny and asks for advice. Leonard deliberately avoids Stuart’s request, and ultimately gives him bad advice. The next day, Leonard feels guilty and goes to apologize to Stuart. Stuart reveals the date went really fine, until he and Penny started making out in his car and Penny accidentally called him "Leonard."

Sheldon wins a National Science Foundation grant to go on a three-month expedition to the Magnetic North Pole to detect magnetic monopoles and prove the validity of string theory. After some hesitation, he decides to go and also wants Leonard, Howard and Raj to come with him; they too initially hesitate as it would mean being locked in a cabin with Sheldon for three months, but they finally agree. To prepare for the expedition, Sheldon and the guys use the freezer at the Cheesecake Factory, however this later proves unnecessary as they are going to spend their entire time in a warm cabin. On the night before the expedition, Leonard expresses doubts on his coming on the expedition as it would mean that he would not see Penny for the whole summer and he also thinks that Penny is going to miss him after she gives him a blanket with sleeves and a long hug, but Sheldon rubbishes the theory. The next morning, when Leonard asks Penny what her actions the previous day meant, she claims to simply have wished him a safe trip, but after he closes the door, she sadly whispers "It means I wish you weren’t going". Meanwhile, in the Arctic, the boys abide to the same rules as in the apartment. Sheldon hides a snack away from Leonard, and pulls another "Bazinga".