Leonard Shelby (GUY PEARCE) is a former insurance investigator turned amateur detective who's searching for the man who raped and murdered his wife some time ago. The only problem is that he was also injured during that attack, leaving him with no short-term memory retention. Although he knows who he is and can recall everything from before the attack, he can't remember anyone he meets or any fact he uncovers for more than a few minutes.
To compensate, he records his meetings and discoveries with Polaroid snapshots, as well as notes written on paper and tattooed on his body. Nevertheless, he's never sure of any new information or people he meets, including Teddy (JOE PANTOLIANO) who claims to be a cop helping him, or Natalie (CARRIE-ANNE MOSS), a barmaid who may or may not have ulterior motives in assisting him in his search.
As he recalls investigating a case from his past involving a man, Sammy Jankis (STEPHEN TOBOLOWSKY) who similarly claimed to have no short term memory, Leonard tries to find his wife's killer despite his memory problem, all while we watch the story unfold in reverse chronological order.