John Murdoch awakens alone in a strange hotel to find that he has lost his memory and is wanted for a series of brutal and bizarre murders. While trying to piece together his past, he stumbles upon a fiendish underworld controlled by a group of beings known as The Strangers who possess the ability to put people to sleep and alter the city and its inhabitants. Now Murdoch must find a way to stop them before they take control of his mind and destroy him.

James Cole, a prisoner of the state in the year 2035, can earn parole if he agrees to travel back in time and thwart a devastating plague. The virus has wiped out most of the Earth's population and the remainder live underground because the air is poisonous. Returning to the year 1990, six years before the start of the plague, Cole is soon imprisoned in a psychiatric facility because his warnings sound like mad ravings. There he meets a scientist named Dr. Kathryn Railly and Jeffrey Goines, the mad son of an eminent virologist. Cole is returned by the authorities to the year 2035, and finally ends up at his intended destination in 1996. He kidnaps Dr. Railly in order to enlist her help in his quest. Cole discovers graffiti by an apparent animal rights group called the Army of the Twelve Monkeys, but as he delves into the mystery, he hears voices, loses his bearings, and doubts his own sanity. He must figure out if Goines, who seems to be a raving lunatic, holds the key to the puzzle.

Dennis Dimbleby Bagley is a brilliant young advertising executive who can't come up with a slogan to sell a revolutionary new pimple cream. His obsessive worrying affects not only his relationship with his wife, his friends and his boss, but also his own body - graphically demonstrated when he grows a large stress-related boil on his shoulder. But when the boil grows eyes and a mouth and starts talking, Bagley really begins to think he's lost his mind. But has he?

In a totalitarian society in a near future, the undercover detective Bob Arctor is working with a small time group of drug users trying to reach the big distributors of a brain-damaging drug called Substance D. His assignment is promoted by the recovery center New Path Corporation, and when Bob begins to lose his own identity and have schizophrenic behavior, he is submitted to tests to check his mental conditions.

Sam Bell has a three year contract to work for Lunar Industries. For the contract's entire duration, he is the sole employee based at their lunar station. His primary job responsibility is to harvest and periodically rocket back to Earth supplies of helium-3, the current clean and abundant fuel used on Earth. There is no direct communication link available between the lunar station and Earth, so his only direct real-time interaction is with GERTY, the intelligent computer whose function is to attend to his day to day needs. With such little human contact and all of it indirect, he feels that three years is far too long to be so isolated; he knows he is beginning to hallucinate as the end of his three years approaches. All he wants is to return to Earth to be with his wife Tess and their infant daughter Eve, who was born just prior to his leaving for this job. With two weeks to go, he gets into an accident at one of the mechanical harvesters and is rendered unconscious. Injured, he awakens back at the station in the infirmary, he assumes assisted by GERTY. GERTY tells him that a rescue team named Eliza will come to the station to clean up the aftermath of the accident. After his recuperation, he takes an unauthorized trip back to the broken harvester, where he makes an unexpected discovery. Because of his find, he begins to doubt his sanity, then his true identity, then the company and GERTY's willingness to do what is best for him. Because of his resulting beliefs, his sole mission becomes how to get back to Earth on his own.

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