4400 centers on the return of 4400 people who, previously presumed dead or reported missing, reappear on Earth. Though they have not aged physically, some of them seem to have deeper alterations ranging from superhuman strength to an unexplained healing touch. A government agency is formed to track the 4400 people after one of them commits a murder.

Thanks to his police officer father's efforts, Shawn Spencer spent his childhood developing a keen eye for detail (and a lasting dislike of his dad). Years later, Shawn's frequent tips to the police lead to him being falsely accused of a crime he solved. Now, Shawn has no choice but to use his abilities to perpetuate his cover story: psychic crime-solving powers, all the while dragging his best friend, his dad, and the police along for the ride.