A woman who moves into an apartment across the hall from two brilliant but socially awkward physicists shows them how little they know about life outside of the laboratory.

Leonard Hofstadter and Sheldon Cooper are both brilliant physicists working at Cal Tech in Pasadena, California. They are colleagues, best friends, and roommates, although in all capacities their relationship is always tested primarily by Sheldon's regimented, deeply eccentric, and non-conventional ways. They are also friends with their Cal Tech colleagues mechanical engineer Howard Wolowitz and astrophysicist Rajesh Koothrappali.

The foursome spend their time working on their individual work projects, playing video games, watching science-fiction movies, or reading comic books. As they are self-professed nerds, all have little or no luck with women. When Penny, a pretty woman and an aspiring actress from Omaha, moves into the apartment across the hall from Leonard and Sheldon's, Leonard has another aspiration in life, namely to get Penny to be his girlfriend.