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."
Science has also interfered with the characters' romantic lives. Leslie breaks up with Leonard when he sides with Sheldon in his support for string theory rather than loop quantum gravity. When Leonard joins Sheldon, Raj, and Howard on a three-month Arctic research trip, it separates Leonard and Penny at a time when their relationship is budding. When Bernadette takes an interest in Leonard's work, it makes both Penny and Howard envious and results in Howard confronting Leonard, and Penny asking Sheldon to teach her physics. Sheldon and Amy also briefly end their relationship after an argument over which of their fields is superior.
Howard and Bernadette learn their second child will be a boy, leading Howard to doubt whether he can be a good father to a son. He and Sheldon go out in the desert to test launch a model rocket, but it explodes, causing him further doubt. On the way home, Howard does a good job coaching Sheldon to drive them home, for which Sheldon tells him he will be a good teacher to his son. Leonard's mother Beverly begins talking to Penny as a friend and confidant, troubling Leonard, especially when he learns that Beverly told Penny that she was proud of her, a level of praise she never bestowed upon Leonard himself. When Leonard confronts Beverly, he is touched when she says that of all of her children's spouses, Penny is the one by whom she is most impressed and that, for this, she is indeed proud of him. Meanwhile, Raj helps Bernadette turn baby girl clothes into boy ones.
The show's pilot episode premiered on September 24, 2007. This was the second pilot produced for the show. A different pilot was produced for the 2006–07 television season but never aired. The structure of the original unaired pilot was substantially different from the series' current form. The only main characters retained in both pilots were Leonard (Johnny Galecki) and Sheldon (Jim Parsons), who are named after Sheldon Leonard, a longtime figure in episodic television as producer, director and actor. A minor character, Althea (Vernee Watson), appeared in the first scene of both pilots that was retained generally as-is. The first pilot included two female lead characters - Katie, "a street-hardened, tough-as-nails woman with a vulnerable interior" (played by Canadian actress Amanda Walsh) and Gilda, a scientist colleague and friend of the male characters (played by Iris Bahr). Sheldon and Leonard meet Katie after she breaks up with a boyfriend and they invite her to share their apartment. Gilda is threatened by Katie's presence. Test audiences reacted negatively to Katie, but they liked Sheldon and Leonard. The original pilot used Thomas Dolby's hit "She Blinded Me with Science" as its theme song.
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".