The plot involves a group of radical pirates who seek the freedom to live under the articles set out by Captain James Misson.

The cities of the title mimic and parody real places, and Burroughs makes references to the United States, Mexico, and Morocco.

The novel is narrated from two different standpoints; one set in the 18th century which follows a group of pirate boys led by Noah Blake, who land in Panama to liberate it.

About a Chinese officer in Tibet... a description of his training in Academy 23... and what he finds in the monasteries would make a buzzard crack his carrion... deliberately using places I have never been to.

Morgan concludes that Cities of the Red Night is, "certainly the most compelling and inventive of Burroughs' books since Naked Lunch.