Memento is presented in two alternating sequences of scenes; one set of scenes, filmed in black and white, progresses forward, while the second set of scenes are in color and presented in reverse order; the two sequences "meet" at the end of the film, thus overall describing one common story.
The main character of the story is Leonard Shelby, a man that suffers from anterograde amnesia, causing him to lose his memories of recent events, unable to form new memories for himself. As the black-and-white narrative opens, he finds himself in a hotel room with instructions from himself to shave a portion of his body and tattoo information onto it, similar to numerous other tattoos he has. As he does this, he receives a phone call, and proceeds to tell the caller of what he remembers. Leonard was an insurance claims investigator, and was assigned the case of Sammy Jankis, a man who seemed to be suffering from anterograde amnesia. Leonard explains how Sammy's inability to even learn via conditioning makes him unable to allow Sammy to get compensation, expressing how he felt Sammy's condition could not be physical in nature, suggested his condition was simply psychological. Out of a mixture of grief and desire to know if her husband's condition was sincere, one day, Sammy's wife asked him for a shot of insulin every few minutes, pretending each one was her first. If her husband's condition were real, he would continue to give her insulin even though it would kill her. The overdose was fatal. Later, Leonard and his wife are attacked by an unknown assailant, causing his wife to die from a fatal wound while Leonard becomes afflicted with anterograde amnesia. Keeping Sammy's case close in mind, Leonard has tried to discover his wife's attacker, using a system of Polaroid photographs and tattoos on his body to retain information that he needs, such as the attacker being known as "John G.", and allowing him to overcome his amnesia.
During the call, Leonard realizes that his tattoos have told him never to answer the phone, and quickly tries to hang up; the caller, insists that he is a cop and that he needs to meet with Leonard. Leonard meets Officer Gammell in the lobby, though Gammell insists that Leonard calls him Teddy since he is undercover. Teddy reveals that a man named Jimmy Grantz is the second attacker and sends Leonard to a desolate buidling to meet and there Leonard kills Jimmy on Teddy's word, taking a photo of the scene. At this point, the two separate sequences in the movie overlap, as the photo of dead Jimmy develops. As Leonard leaves, Teddy tries to convince Leonard that he has conditioned himself to continue his quest for vengeance. Teddy also insists that Leonard is confusing elements of Sammy's story with his own, Sammy having been single and a con man trying to fraud the insurance company; Teddy asserts that Leonard's wife survived the attack and that Leonard later himself administered his wife's overdose of insulin after the onset of his amnesia. After hearing what Teddy states Leonard purposely destoys the photos indicating his quest is done, writes down "don't believe his lies" on Teddy's photograph and leaves a note to himself to get a tattoo with Teddy's license plate implicating him as his wife's attacker, even though his voiceover indicates he does not believe Teddy is the second attacker. He then leaves in Jimmy's car. As his amnesia sets in, he comes across a tattoo parlor [which is the end of the film proper, but this is where the film begins to go into reverse scene order] and follows his instructions with regards to Teddy's license plate.
Without other clues to go on, Leonard goes to a bar listed on a coaster in Jimmy's car. At the bar, he meets Natalie, Jimmy's girlfriend, who is initially hostile to Leonard wondering why Leonard is at the bar in Jimmy's car and wearing Jimmy's clothes. However, as Leonard explains his situation, Natalie realizes she can manipulate Leonard, turning him on a man named Dodd that she claims has been trying to harass her in order to get back at Jimmy. Leonard is able to track Dodd down and capture him; with Teddy's help, they force him to leave town. Again, Teddy attempts to warn Leonard of his dangerous quest, but Leonard refuses to listen based on his own comment scrawled on Teddy's photograph. Leonard returns to Natalie, and the two spend the night together, with Natalie promising to retrieve the driver's license of the car that his latest tattoo is registered to. They meet the next afternoon and she provides Leonard with the information as well as a desolate location in order to kill him. Leonard finds the information points to Teddy, whose real name is "John Edward Gammell", matching all the facts of the case based on his tattoos; his own warning on Teddy's picture affirms his suspicions. He lures Teddy to the same desolate building where he killed Jimmy, and proceeds to kill Teddy, taking a picture of dead Teddy just like he took a picture of dead Jimmy. This scene is the opening scene of the movie behind the movie credits, and is the only scene in the movie that played in reverse.