When Penny tells Leonard he needs to be more assertive in making decisions for himself, he starts standing up to Sheldon over small things. His confidence makes him want to demand the university support his idea for a plasma physics project. He threatens to quit if the university refuses, alarming both Sheldon and Penny, who consider this to be a risky career move. Sheldon is conflicted on whether or not he is being selfish over Leonard's decision, but Amy suggests that the fact that he is worried over Leonard's motivation proves that he does care about him, which he acknowledges. President Seibert refuses the project, but in order not to lose Leonard, gives him co-leadership over a photon entanglement project, leaving Leonard proud of himself and Penny impressed. Meanwhile, Raj shows Anu his lab, and suggests one possible answer for something he's seen in space might be alien life. When someone mentions this at his observatory presentation, the scientific community starts mocking him as a conspiracy theorist. Raj points out scientists should consider all possibilities when seeking the truth, though this causes people to think he believes in the Loch Ness Monster.
Professor Proton, Sheldon's favorite childhood show, is being rebooted. After unsuccessfully auditioning for the part, he goes to Wil Wheaton for acting tips for his second audition. However, Sheldon is later dismayed when Wil is offered the role instead. Talking it over with Arthur in his dreams, he is still upset to see his idol replaced and considers Wil an enemy again. Meanwhile, Howard gets a vasectomy while Bernadette is on bed rest. Penny offers to take care of Halley for them, but they insult her by expecting her to be irresponsible. Halley ends up saying her first word by calling Penny "Mama."
Sheldon and Amy are surprised to find that Wil Wheaton's new Professor Proton show is actually very entertaining and that Wil had Howard on as a guest. On Howard's suggestion, Sheldon apologizes to Wil, mending their friendship, and tells him he wants to be on the show; but Wil asks for Amy. Sheldon tells her to do it, but she says she often doesn't do things to avoid upsetting him. Sheldon is horrified when he realises how selfish he has been, especially when he finds out that the men do the same for him. Sheldon encourages Amy to go on the show to inspire girls to pursue science while trying to control his obvious jealousy for her. Meanwhile, Leonard writes a book about a physicist that solves a murder, the protagonist Logan Dean is based on himself. Bernadette points out Logan's mean boss Illsa is similar to Penny, who thinks it is based on Bernadette, though Leonard does not correct her. However, Bernadette tells Penny the truth, upsetting her and making her mad at Leonard. After calling his mother for advice, Leonard learns that Illsa is actually like her; but abandons the book when he realizes he wrote romantic tension into the relationship between the characters.
Kunal Nayyar as Rajesh Koothrappali: A particle astrophysicist originally from New Delhi, India. Raj is initially unable to talk to women unless he drinks alcohol. Raj also has very feminine tastes and often takes on a stereotypical female role in his friendship with Howard as well as in the group of four men. Raj later dates Lucy (Kate Micucci), who also suffers from social anxiety, but it eventually ends; he later speaks to Penny without alcohol and thus overcomes his selective mutism. He begins dating Emily and their relationship later becomes exclusive. Raj also has a Yorkshire Terrier named Cinnamon.
Leonard and Sheldon are brilliant physicists—geniuses in the laboratory but socially challenged everywhere else. Enter beautiful, street-smart neighbor Penny, who aims to teach them a thing or two about life. Despite their on-again, off-again relationship in the past, Leonard and Penny have finally gotten married. Even Sheldon has found a female companion, entering into a "relationship agreement" with neurobiologist Amy Farrah Fowler, and he recently took their relationship to the next level by marrying her after a long courtship. In their free time, Leonard and Sheldon enjoy fantasy role-playing games with their ever-expanding universe of friends, including fellow scientists Koothrappali, Wolowitz, and Wolowitz’s adorable microbiologist wife, Bernadette, who is adjusting to life with their two children.
Wil Wheaton brings William Shatner on his Professor Proton show to meet Sheldon, who gets so excited that he vomits on Shatner. Going to Wil to apologize, he finds Wil hosts a Dungeons & Dragons group with his celebrity friends including Shatner. Finding out Stuart is in the group and never told them, the guys make Stuart panic and quit. Wil secretly invites Leonard who discovers that the group also includes Shatner, Kevin Smith, Joe Manganiello and Kareem Abdul-Jabbar. Leonard tells Penny, who tells Amy and Bernadette, all three women having a crush on Manganiello. Because of that indiscretion, Wil kicks out Leonard and admonishes the guys for using him for his connections, and says that one of the worst things about being a celebrity is not knowing whether someone will like him for himself. To apologize, the guys invite Wil to play D&D with them at Leonard’s apartment, but Wil, secretly in the middle of a game with Penny, Amy and Bernadette and the group, politely turns them down, before allowing the girls to send them a photo of the events as payback.
Sheldon's mother Mary refuses to attend his wedding unless he invites his older brother George, with whom he is no longer speaking. Sheldon and Leonard fly to Texas to talk to George, who now owns a chain of tire stores. He refuses to attend and later explains to Leonard and Sheldon that the family sacrificed a lot to fund Sheldon's education, and he was stuck caring for their mother and sister Missy after their father died while Sheldon was in college. Sheldon never thanked him for this. Leonard takes George back to the hotel room where Sheldon apologizes for what he did and the brothers reconcile. George agrees to attend the wedding. Meanwhile, Howard and Bernadette's children contract pinkeye, infecting everyone except Penny, much to Amy's fury.
The scene is all business – at least as much as you can expect from a bunch of cut-ups making a sitcom – and no one seems distracted by two significant events: The episode will mark the show’s 276th, moving it past “Cheers” to set a record for a sitcom filmed in front of a studio audience, and only three more remain to be shot for "Big Bang," co-created by Chuck Lorre and Bill Prady.
Producers, writers and others, including recurring guest star Wil Wheaton, joined the festivities on set and — hardly a spoiler alert — more laughing, crying and hugging ensued. Lorre embraced a happy Parsons, then moved on to each cast member as if it were a reception line. Galecki shared long, emotional hugs with his colleagues. After trying to keep their emotions under control for so long, it was finally time to just let go.
Penny runs into her ex-boyfriend Zack, who has gotten rich from selling his company and married a similarly dim-witted woman named Marissa. Meeting with Leonard and Penny, they say Zack is infertile and ask to pay Leonard as a sperm donor so they can have a baby. Leonard is flattered, but Penny finds it creepy. Leonard says that since Penny decided she did not want to have children, he should be allowed to help another couple with this issue. Sheldon advises him to think about the emotional toll this could have on him. Leonard says he will not do it if Penny objects; Penny says she will support whatever decision Leonard makes. Meanwhile, Raj tries to get Anu back but she points out he just wanted to be married like his friends. Raj points out that Anu is similarly looking for a quick marriage. He admits to Anu that he really likes her and they decide to start their relationship as just dating.
Sara Gilbert as Leslie Winkle (recurring season 1, starring season 2, guest seasons 3, 9): A physicist who works in the same lab as Leonard. In appearance, she is essentially Leonard's female counterpart and has conflicting scientific theories with Sheldon. Leslie has casual sex with Leonard and later Howard. Gilbert was promoted to a main cast member during the second season but resumed guest star status because producers could not come up with enough material for the character. Gilbert returned to The Big Bang Theory for its 200th episode.
Sheldon has been writing to the reclusive scientist Dr. Wolcott (Peter MacNicol) who invites Sheldon to visit him in his completely isolated mountain cabin. The women quickly ask Leonard, Raj and Howard to tag along with him, making this his bachelor party, despite Sheldon's assertions that it shouldn't be called such. Wolcott has a brilliant mind but his behavior is very strange to the guys. He tells Sheldon he cut off all contact with others to focus on science. Though Sheldon enjoys the science, he decides that he doesn't want to live like Wolcott because of his friends and Amy. The guys leave to avoid Wolcott, whose theories about time make him doubt whether the guys were ever there. Meanwhile, Penny and Bernadette throw Amy a quilting bee for her bachelorette party, which she quickly finds boring. When Amy tells them she wants a night full of bad decisions as she earlier implied, they go to a bar where Amy drinks a few shots and passes out in twelve minutes. When she wakes up back at the apartment hungover and disappointed, the women lie and reassure her she had a wild time, involving her drunkenly riverdancing.
Simon Helberg as Howard Wolowitz: An aerospace engineer who got his Masters at MIT. Howard is Jewish and lived with his mother, Debbie (Carol Ann Susi). Unlike Sheldon, Leonard, Raj, Bernadette and Amy, Howard does not hold a doctorate. He goes into space, training as an astronaut and serving as a payload specialist. Howard initially fancies himself as a womanizer, but he later starts dating Bernadette, and they get engaged and married. Howard also has a tendency to waste money on toys and argues with Bernadette because of his oddly low income as an engineer and her high income as a pharmaceutical biochemist.