The medical condition experienced by Leonard in this film is a real condition called Anterograde Amnesia - the inability to form new memories after damage to the hippocampus. During the 1950s, doctors treated some forms of epilepsy by removing parts of the temporal lobe, resulting in the same memory problems.
Christopher Nolan's screenplay was based on his brother Jonathan Nolan's story "Memento Mori". But the screenplay is still considered original (rather than adapted) because Jonathan's story wasn't published until after the film was completed.
EASTER EGG: in the Limited Edition DVD (and in the standard Region 2 edition) allows the movie to be watched in the exact chronological order of the events in the film. The first couple scenes of the regular cut of the movie appear normal in this version, meaning they are not reversed. However, this version of the movie is on Disc 2, is quite difficult to reach (the user must answer several questions and solve a puzzle), and forward, reverse and chapter skip capabilities are disabled.
"Paranoid Android" by Radiohead was originally going to be used in the closing credits, but Christopher Nolan decided that the royalties needed to use this song (owned by Capitol Records) would be too great for this low-budget film.
Chronology: When numbering the scenes chronologically, then sorting them how they appear in the film, the pattern becomes more clear. The letters A-V will represent the color scenes (with A happening chronologically first, and V chronologically last), and the numbers 1-22 represent the black and white scenes chronologically. The scenes appear in the film like this: 1, V, 2, U, 3, T, 4, S, 5, R, 6, Q...20, C, 21, B, 22/A The two types of scenes alternate. The black and white scenes (numbers) start from the very beginning soon after the injury, and work forward to the climax at 22/A, while the color scenes (letters) work backward from the climax at 22/A. The climax scene (22/A) changes to color halfway through, showing the convergence of the two story lines.
Stephen Tobolowsky has stated that during his audition for Sammy, he had mentioned to Director Christopher Nolan that he had experienced amnesia personally. A few years earlier, he was given an experimental pain killer that induced amnesia for a surgery he had undergone. Tobolowsky said it may have helped him get the part because no other actor would likely have had his first hand experience.
The test given to Sammy Jenkis involving the electrified objects is based on a real life case study of a patient commonly referred to as HM, who suffered from the same form of amnesia following surgery to treat severe epilepsy. A doctor repeatedly shook HM's hand with a joy buzzer, shocking him every time. After a few trials, HM refused to shake hands. The test shown in the movie is an illustration that Sammy's condition was not identical to a real life case study, but would not have excluded him from insurance coverage.
During Teddy's line "You don't have a clue, you freak!", director Christopher Nolan felt that Joe Pantoliano, who played Teddy, did not quite nail the end of the line, so he decided to rerecord the last two words to his liking, delivering them himself. Therefore, in the final film, the words "you freak", as we hear them, are actually being said not by Pantoliano, but by Nolan impersonating Pantoliano's voice. Pantoliano was unaware of the dubbing until an interview for the show Anatomy of a Scene.
After being impressed by Carrie-Anne Moss' performance as Trinity in the 1999 science fiction film The Matrix, Jennifer Todd suggested her for the part of Natalie. While Mary McCormack lobbied for the role, Christopher Nolan decided to cast Moss as Natalie, saying, "She added an enormous amount to the role of Natalie that wasn't on the page".
The picture of Leonard that Leonard finds in the envelope under his motel door shows him pointing at a bare spot on his chest. He tells Natalie that this spot is reserved for when he finds John G. Later, when Leonard is driving to the tattoo parlor, he thinks about his wife, and a flashback is shown in which he is lying in bed with his wife. The bare spot in this shot now contains: "I've done it."
After his wife's death, Sammy is shown sitting in a mental institution. Briefly, just after someone walks in front of him and before the scene cuts back to Leonard on phone, Sammy's character is actually replaced by Leonard sitting in the same chair. This supports the conclusion, that the tragic end of Sammy's story is actually an event from Leonard's own past, just as Teddy later tries to convince him.
While Leonard is watching TV at Natalie's, a picture of a needle with a person wearing a white v-neck shirt in the background can be seen. In the story of Sammy Jankis, Sammy injects his wife with insulin while he watches TV. This alludes to the possibility that Sammy Jankis's story is really Leonard's own. Moreover, the white v-neck in the background is the same shirt that Leonard's wife wears in another scene.
During Leonard's third and final conversation with the anonymous caller, his fingers hover over the numbers 555-0134. This is Teddy's phone number, which is on the bottom of his photograph, thus hinting that Leonard is actually talking to Teddy.