One of the recurring plot lines is the relationship between Leonard and Penny. Leonard becomes attracted to Penny in the pilot episode and his need to do favors for her is a frequent point of humor in the first season. Meanwhile, Penny dates a series of muscular, attractive, unintelligent, and insensitive jocks. Their first long-term relationship begins when Leonard returns from a three-month expedition to the North Pole in the season 3 premiere. However, when Leonard tells Penny that he loves her, she realizes she cannot say it back. Both Leonard and Penny go on to date other people; most notably with Leonard dating Raj's sister Priya for much of season 4. This relationship is jeopardized when Leonard comes to falsely believe that Raj has slept with Penny, and ultimately ends when Priya sleeps with a former boyfriend in "The Good Guy Fluctuation".
Laura Spencer as Emily Sweeney (recurring seasons 7–8, 10, starring season 9): A dermatologist at Huntington Hospital. Emily went to Harvard and delights in the macabre and states that she likes her job because she can cut things with knives. Prior to meeting Raj, Emily was set up on a blind date with Howard. After finding Emily's online dating profile, Raj has Amy contact her as his wingman instead. Their relationship becomes exclusive, but Raj later breaks up with Emily when he becomes infatuated with the bartender Claire (Alessandra Torresani).
Penny, who admits to missing Leonard in "The Roommate Transmogrification", accepts his request to renew their relationship in "The Beta Test Initiation". After Penny suggests having sex in "The Launch Acceleration", Leonard breaks the mood by proposing to her. Penny says "no" but does not break up with him. She stops a proposal a second time in "The Tangible Affection Proof". In the sixth-season episode, "The 43 Peculiarity", Penny finally tells Leonard that she loves him. Although they both feel jealousy when the other receives significant attention from the opposite sex, Penny is secure enough in their relationship to send him off on an exciting four-month expedition without worrying in "The Bon Voyage Reaction". After Leonard returns, their relationship blossoms over the seventh season. In the penultimate episode "The Gorilla Dissolution", Penny admits that they should marry and when Leonard realizes that she is serious, he proposes with a ring that he had been saving for years. Leonard and Penny decide to elope to Las Vegas in the season 8 finale, but beforehand, wanting no secrets, Leonard admits to kissing another woman, Mandy Chow (Melissa Tang) while on an expedition on the North Sea. Despite this, Leonard and Penny finally elope in the season 9 premiere.
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."
"The Locomotive Manipulation" is the first episode in which Sheldon initiates a kiss with Amy. Although initially done in a fit of sarcasm, he discovers that he enjoys the feeling. Consequently, Sheldon slowly starts to open up over the rest of the season, and starts a more intimate relationship with Amy. However, in the season finale, Sheldon leaves temporarily to cope with several changes and Amy becomes distraught. However, in "The Prom Equivalency", he hides in his room to avoid going to a mock prom reenactment with her. In the resulting stand-off, Amy is about to confess that she loves Sheldon, but he surprises her by saying that he loves her too. This prompts Amy to have a panic attack.
Sheldon's childhood friend from Texas, Tam, is visiting the university with his son. Sheldon does not want to see him and the others wonder why Sheldon has never mentioned Tam. Tam is unaware Sheldon is angry with him, thinking they just naturally drifted apart. Sheldon's brother George does not know the reason either. Sheldon eventually reveals Tam promised he would move to California with Sheldon, but then got a girlfriend and stayed with her, leaving Sheldon feeling abandoned. Tam and Sheldon make up and Sheldon has Leonard take Tam to the airport. Meanwhile, Penny and Bernadette want to get to know Anu, impressed by her connections in the hotel industry. They tell her embarrassing things about Raj and wonder if they can go out with her again after Raj confronts them.
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.
After learning Sheldon went behind their backs to work with the military again, Leonard and Howard say Sheldon is like Thomas Edison, taking credit for others' ideas, while they are more like Nikola Tesla. Leonard and Howard bring in Barry Kripke to help create a better idea than Sheldon's, but Kripke goes to the military himself, cutting all three of them out. Meanwhile, Bernadette fears Ruchi is trying to steal her projects at work while she is on maternity leave and enlists Raj to spy on her. Though he finds proof that Ruchi may be stealing from Bernadette, Raj tries to defend Ruchi like a boyfriend would, pointing out Bernadette's hypocrisy as she would most likely have stolen from other people's projects as well. Ruchi is not happy about this and promptly dumps Raj.
In March 2017, CBS renewed the series for two additional seasons, bringing its total to twelve, and running through the 2018–19 television season. On August 22, 2018, CBS and Warner Bros. Television officially announced that the twelfth season would be the series' last. This stems from Jim Parsons' decision to leave the series at the end of the season if the show were to have been renewed for a thirteenth season. The series concluded with an hour-long finale consisting of two back-to-back episodes on May 16, 2019. A retrospective, hosted by Johnny Galecki and Kaley Cuoco, aired at 9:30 P.M. ET/PT, the night of the finale, following the season two finale of Young Sheldon.
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.
Howard and Raj are still fighting, so Howard dis-invites Raj to Halley's birthday party. However, when Stuart pulls out as party planner at the last minute, Raj agrees to plan the party, which doesn't turn out too well due to Halley being asleep, Bernadette being on bed rest, and no people turning up. When Howard and Raj get into a shoving match in the party's bounce house, they end up letting out their frustrations, but also having fun and reconciling. Leonard is depressed upon receiving his successful brother's Christmas card and attempts to make a list of what he and Penny accomplished this year, not coming up with much. This prompts them to think about their plans for the future, so they decide to go on trips and achieve more out of life together before starting a family. Sheldon cooks Amy a Little House on the Prairie-themed birthday dinner, which gives them both food poisoning. They eventually recover enough to attend Halley's birthday party with the others, where they have fun in the bouncy castle and then have sex in Howard and Bernadette's house.
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.
Sheldon needs half a billion dollars to prove his latest concept of string theory, which the University cannot afford to fund. Crowdfunding and selling some of his most valuable comic books to Stuart give him a small start. When Raj mentions gambling in Las Vegas, Sheldon goes there but is caught calculating odds by security before he can make any bets. Meanwhile, Amy takes Penny and Bernadette shopping for her wedding dress. She loves an old-fashioned one that the other girls admit that they find ugly, though Penny assures Amy she can make her own decisions about her wedding. Sheldon, however, comes home and sees Amy in the dress and loves how she looks.