The sitcom is centered on five characters living in Pasadena, California: roommates Leonard Hofstadter and Sheldon Cooper; 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.

The world's leading deception researcher, Dr. Cal Lightman, studies facial expression, body language and tone of voice to determine when a person is lying and why, which helps law enforcement and government agencies uncover the truth. But his skills also make it easier for him to deceive others.

Dr. Temperance Brennan and her colleagues at the Jeffersonian's Medico-Legal Lab assist Special Agent Seeley Booth with murder investigations when the remains are so badly decomposed, burned or destroyed that the standard identification methods are useless.