In the Near Future, conflicts between various countries results in all of them launching a variety of weapons at each other all at once. The resulting unpredictable combination of side effects wiped out the majority of the population and turned most of the Earth's surface into The Great Waste. The survivors were divided up into roughly two groups: those who became mutants (or were immune to mutations), and those not yet exposed to the mutagen. The first group, collectively known as "mutants", either roam the surface raiding city ruins for food, or live in survival bunkers. One such bunker, located a mile underground, is Endtown. The second group are the "Topsiders", highly prejudiced "pure humans" who live in undisclosed locations and hunt mutants with the goal of ridding the planet of them. The Endtown story revolves around one group of mutants attempting to survive under these conditions.

The Endtowners, as they call themselves, spend most of their time in the underground city, with occasional forays to the surface to scavenge for food. Because of the effects of the post-War radiation, most protein-based foods have turned to dust, leaving only those items still in cans. At the time in which the story is set, six years after The End, cans of beans are all that remain in the ruins reachable by foot. Endtowners only have a synthetic "vitamin cake" and beans to live on. The lack of variety in their diet drives many of the Endtowners to desperation.

The mutagenics' effects do seem to follow some form of rules, though from the outside the effects appear unpredictable. Humans are often turned into monsters, though the luckier ones can become animals. Species shown so far include a rhino, several breeds of cats, mice, rats, crabs, fish, dogs, cows and at least one worm. The more bizarre but benign mutations include a hunchback with a fish head that falls off (and presumably grows back), and the Oracle, a precognitive pool of water. There is a series of canals in Endtown to support the water supply and sewage carry-away, as well as providing the aquatic species a place to live. On the surface of the planet, the Topsiders wear sealed suits to protect themselves from the tainted atmosphere. If the suit is damaged, the victim begins to mutate within seconds.

In the story, Endtown is described as a form of commune where the inhabitants provide various services in return for housing and food. Most services are along the lines of working at a cafe, or acting as a doctor, police officer or main entrance gate security. Greater rewards are offered for Topside scavenging missions, but the odds of not surviving one of these missions are very high.

Topsiders hunt mutants as part of their eugenics campaign for two known reasons: to eliminate them from the planet and to put their brains into machines such as the transport vehicles, blaster guns, and robot tracking devices called "Multi-Use Terrestrial Trackers" (AKA: "MUTTS").