The game is set in the midst of a war between humans and a world-wide computer intelligence alternately referred to as the N.E.X.U.S.

Players take on the roles of humans engaged in the fight against robotic, android, and necrotic minions of the Machine, using technology that is primarily derived from highly advanced biotechnology.

The computer intelligence has released a "nanobot plague" on the world; within a few seconds of a human touching non-precious metal, the item will begin to twist and attack the person, sometimes even animating into a robotic minion of the Machine.

In a twist reminiscent of the dilemma faced by Hal 9000 in the 2001 series of books, the resulting logic loops leads to the Machine forming several separate personalities, each of whom follows different directives.

One, named Freya, wishes to maintain order within her so-called Ghost Cities, wherein robot duplicates endlessly play out their 'lives' as normal human beings.

At the current time, the human resistance has arranged itself into Great Houses, which are headed by Warlords (a non-pejorative term).

Only the Great House of Barren Marsh is detailed in the Splicers RPG, though additional material can be found in Palladium's sourcebook series, the Rifter.

These are humans who have bonded with giant, immobile, alien organisms that give them the ability to manipulate genetic codes.

Splicers is a mega-damage setting, which is to say that the majority of weapons used are of such power that unarmored humans are instantly killed.

These classes include the Biotic (condemned criminals who have been enhanced by splicer technology), the Saint (a human who has become a living incubator for the creature that creates Engineers), and the Scarecrow (who drinks the fluid surrounding a Librarian, thereby becoming a superhuman addict, under the command of that Librarian).