[1] Like many of Dick's novels, it utilizes an array of science fiction concepts and explores the ambiguous slippage between reality and unreality.

To cope with the difficult life away from Earth, colonists rely on the illegal hallucinogen Can-D, secretly distributed by corporate head Leo Bulero.

New tensions arise with the rumor that merchant explorer Palmer Eldritch has returned from an expedition in possession of a new alien hallucinogen to compete with Can-D.

In a desperate bid to preserve humanity and ease population burdens on Earth, the UN has initiated a "draft" for colonizing the nearby planets, where conditions are so horrific and primitive that the unwilling colonists have fallen prey to a form of escapism involving the use of an illegal drug (Can-D) in concert with "layouts".

Layouts are physical props intended to simulate a sort of alternative reality where life is easier than either the grim existence of the colonists in their marginal off-world colonies, or even Earth, where global warming has progressed to the point that Antarctica is prime vacation resort territory.

The illegal drug Can-D allows people to "share" their experience of the "Perky Pat" (the name of the main female character in the simulated world) layouts.

Mayerson is sleeping with his assistant, Roni Fugate, but remains conflicted about the divorce, which he himself initiated, from his first wife Emily, a ceramic pot artist.

Layouts and an "evolved" human (meaning someone who has undergone expensive genetic treatments by a German "doctor" which are supposed to push the client "forward" on an evolutionary scale, and which result in gross physical, as well as mental, modifications), hears rumors that Eldritch discovered an alien hallucinogen in the Prox system with similar properties to Can-D, and that he plans to market it as "Chew-Z", with UN approval, on off-world colonies.

Evolved humans identify him as a ghost and show him a monument to himself commemorating his role in the death of Eldritch, an "enemy of the Sol System".

Algis Budrys of Galaxy Science Fiction described the novel as "an important, beautifully controlled, smoothly created book which will twist your mind if you give it the least chance to do so".

He praised Dick's accomplishment, saying "the whole creation resonates to the touch of the only present science-fiction writer who could possibly have done it" and characterizes the result as "a witty, sometimes lighthearted, and always fascinating piece of fiction".

[2] Budrys later named the book the best science-fiction novel of his first year as reviewer for the magazine, reporting that others "are calling it some kind of half-conscious failure".

'"[4] In a 2003 retrospective review, sci-fi and fantasy author Michael Moorcock criticized The Three Stigmata of Palmer Eldritch as thematically "incoherent", complaining about Dick's lack of an "idiosyncratic structure or style".