Narrated in a voice that at times may be construed as the author's own, Guide is the story of the conflict between a novelist's fantasy life and his inability to represent it in language. Remembering the clarity and omnipotence he felt during an LSD trip in his teens, "Dennis" drops acid and attempts to write a novel that will make sense of his life, his desires, his friends, and his art, and distinguish what is real from the distortions created by his overactive imagination.

Dennis's sexual relationship with Chris - an addict who fantasizes about being killed - pushes him to the very edge of emotions he has only imagined. His platonic love for Luke, an imaginative, but far more innocent, friend, offers possible salvation from his otherwise crazy life.

In episodic chapters that criss-cross through time, Guide weaves together Dennis's story with these and other characters, including Goof, a young and amazingly innocent porn star, Sniffles, a teenage runaway whose need for love outweighs his attachment to life, and Mason, whose lurid desires are rivaled only by Dennis's own.