The Big Bang theory is an effort to explain what happened at the very beginning of our universe. Discoveries in astronomy and physics have shown beyond a reasonable doubt that our universe did in fact have a beginning. Prior to that moment there was nothing; during and after that moment there was something: our universe. The big bang theory is an effort to explain what happened during and after that moment.

The show is primarily centered on five characters living in Pasadena, California: roommates Leonard Hofstadter and Sheldon Cooper, both physicists; Penny, a waitress and aspiring actress who lives across the hall; and Leonard and Sheldon's equally geeky and socially awkward friends and co-workers, mechanical engineer Howard Wolowitz and astrophysicist Raj Koothrappali. The geekiness and intellect of the four guys is contrasted for comic effect with Penny's social skills and common sense.

Over time, supporting characters have been promoted to starring roles: Leslie Winkle, a physicist colleague at Caltech and, at different times, a lover of both Leonard and Howard; Bernadette Rostenkowski, Howard's girlfriend (later his wife), a microbiologist and former part-time waitress alongside Penny; neuroscientist Amy Farrah Fowler, who joins the group after being matched to Sheldon on a dating website (and later becomes Sheldon's girlfriend); and Stuart Bloom, the cash-strapped owner of the comic book store the characters often visit.