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.
Jim Parsons as Sheldon Cooper: Originally from Galveston, Texas, Sheldon was a child prodigy with an eidetic memory who began college at the age of eleven, and earned a PhD at age sixteen. He is a theoretical physicist researching quantum mechanics and string theory, and despite his IQ of 187, he finds many routine aspects of social situations difficult to grasp. He is determined to have his own way, continually boasts of his intelligence, and has an extremely ritualized way of living. Despite these quirks, he begins a relationship with Amy Farrah Fowler, and they eventually marry.
In scenes set at Howard's home, he interacts with his rarely-seen mother (voiced by Carol Ann Susi until her death) by shouting from room to room in the house. She similarly interacts with other characters in this manner. She reflects the Jewish mother stereotype in some ways, such as being overly controlling of Howard's adult life and sometimes trying to make him feel guilty about causing her trouble. She is dependent on Howard, as she requires him to help her with her wig and makeup in the morning. Howard, in turn, is attached to his mother to the point where she still cuts his meat for him, takes him to the dentist, does his laundry and "grounds" him when he returns home after briefly moving out. Until Howard's marriage to Bernadette in the fifth-season finale, Howard's former living situation led Leonard's psychiatrist mother to speculate that he may suffer from some type of pathology, and Sheldon to refer to their relationship as Oedipal. In season 8, Howard's mother dies in her sleep while in Florida, which devastates Howard and Stuart, who briefly lived with Mrs. Wolowitz.
Kaley Cuoco as Penny: An aspiring actress from Omaha, Nebraska. Penny moves in across the hall from Sheldon and Leonard. She waits tables and occasionally tends the bar at the Cheesecake Factory. After giving up hope of becoming a successful actress, Penny becomes a pharmaceutical sales representative. Penny becomes friends with Bernadette and Amy, and they often hang out in each other's apartments. Penny and Leonard form a relationship and eventually marry.
In the apartment building where Sheldon, Leonard and Penny (and later Amy) live, the elevator has been out of order throughout most of the series, forcing characters to have to use the stairs. Stairway conversations between characters occur in almost every episode, often serving as a transition between longer scenes. The Season 3 episode, "The Staircase Implementation" reveals that the elevator was broken when Leonard was experimenting with rocket fuel. In the penultimate episode of the series, the elevator is returned to an operational state, causing Sheldon some angst.
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.