A Fire upon the Deep by Vernor Vinge tells a tale of human scientists inadvertently releasing an ancient Blight on the universe, and the Blight racing an expedition to find what mystery has escaped their control: a secret that can make the Blight even more powerful or a Countermeasure that can once again defeat it. The world on which the starship carrying the mystery has landed has a medieval social order and dog-like sentient creatures are the dominant species. Two warring factions adopt human siblings who survive the landing, learning from them technology to bring about military victory.

Human scientists, lured by profit, develop a lost, inadvertently releasing the "Straumli Perversion," also known as "the Blight," on computers and sentient beings throughout the High Beyond. The Olsndot family escapes with the colonists' children in suspended animation and a "Countermeasure" that has successfully defeated the Blight aeons earlier. The parents are killed upon landing on a planet deep enough in the Slow Zone to be safe, by the wolf-like inhabitants ("Tines") who function only in packs. Young Johanna and Jefri are seized by rival warring tribes and believe the other is dead. The Flenserists are led by Steel and the southerners by Woodcarver. Society is medieval. Flenser, Steel's creator, supposedly assassinated, comes back as Tyrathect, who impersonates the Master while serving Steel's interests.

The human children befriend their captors and help them develop cannons for defense against the other side's aggression. A pack of puppies, Abdi, helps Jefri contact the rescue starship Out of Band II (OOB), to guide it to the planet in exchange for technology from its library. Woodcarver perfects the same weaponry using Johanna's Dataset. OOB is crewed by humans Ravna Bergsndot and Pham Nuwen and Skroderiders Blueshell and Greenstalk. While stopping for repairs, Blueshell is briefly infected by the Blight and distrusted by Pham once the OOB escapes, tailed by anti-human extremists who have exterminated Sjandra Kei and a large force of Blighters.

A huge surge from the Slow Zone mires them all, but after it passes, the race to Tines' world resumes. The Olsndots are reunited as Woodcarver's forces prevail and Pham, while experiencing "godshatter," becomes integrated with the fungal Countermeasure to concentrate the power needed to produce an even larger surge that engulfs much of the galaxy, sweeping away the Blighters and countless civilizations. It claims Pham's life. Ravna settles into raising the revived children and educating the Tines. News posts suggest that even the infected High Beyond is affected by "Pham's Revenge."