The basic premise of the game is that the player characters are Garou. Specifically player characters usually are supposed to have undergone some training as Garou and succeeded in an initiation rite known as the Rite of Passage. After this, they are considered of Cliath rank (see Rank). Usually the player characters form a pack and work together to gain renown among the other Garou, so that they can advance in rank.
The game takes place in a fictional version of our Earth, a secret world, where werewolves, vampires, and other legendary creatures secretly live beside humans. However, it's a dark reflection of our world filled with corruption, apathy, violence, and hopelessness. The setting is also described as Gothic-Punk.
The Garou battle to maintain this world before all the negativity leads to a total collapse, the titular Apocalypse. They do so hidden from the public eye and live in secret from humanity in general. In their war, the Garou often hunt down and kill humans and supernatural creatures that either actively pursue the Apocalypse or unwittingly contribute to it, due to their parasitic nature. This includes fallen Garou, vampires, evil spirits, mages/sorcerers, and humans (and other creatures) possessed by demons. In doing so, the Garou regard themselves as the immune system of the planet, after a fashion.
Other themes of the game include the inability of the Garou to live as/among humans, although they were born in human form due to The Curse, interaction with spirits that today are separated from the physical world in a realm the Garou can enter.
During the period of the "taming of the West" in America in the 1700-1800s, the Garou engaged in a second War of Rage against not just the Fera of the New World, but against their own brethren, the Native American tribes of Garou (who call themselves the Pure Ones); in this war, the Garou exterminated the Camazotz were-bats and drove their totem, Bat, to madness and the service of the Wyrm. The careless progress of the European Garou (called Wyrmcomers by the Pure Ones) also severed the mystical bonds restraining a powerful bane (a spirit servitor of the Wyrm). This bane captured and devoured a powerful servant of the Weaver, combining their essences and becoming the Storm-Eater. The Storm-Eater whipped the Umbra (the spirit world) of the West into a terrible frenzy resembling an earthly storm, gaining it the nickname "Storm Umbra", and further threatened to bring on an early Apocalypse. The Storm-Eater was eventually re-bound by the sacrifice of 13 Elder Garou and the execution of the Rite of Still Skies (discovered by the Two-Moons pack, led by the Silver Fang Theurge Isaiah Morningkill of House Wyrmfoe).