The book begins by discussing the history of parasites in human knowledge, from the earliest writings about them in ancient cultures, up through modern times. The focus comes to rest extensively on the views and experiments conducted by scientists in the 17th, 18th, and 19th centuries, such as those done by Antonie van Leeuwenhoek, Japetus Steenstrup, Friedrich Küchenmeister, and Ray Lankester. Among them, Leeuwenhoek was the first to ever physically view cells through a microscope, Steenstrup was the first to explain and confirm the multiple stages and life cycles of parasites that are different from most other living organisms, and Küchenmeister, through his religious beliefs and his views on every creature having a place in the natural order, denied the ideas of his time and proved that all parasites are a part of active evolutionary niches and not biological dead ends by conducting morally ambiguous experiments on prisoners. Lankester is given a specific focus and repeated discussion throughout the book due to his belief that parasites are examples of degenerative evolution, especially in regards to Sacculina, and Zimmer's repeated refutation of this idea.
Several chapters are taken to discuss various types of parasites and how they infect and control their hosts, along with the biochemistry involved in their take-over or evasion of their hosts immune system, eventually leading to their dispersal into their next form and life cycle. An extended time is also given on the workings of immunology and how the immune systems of living beings respond to parasite infection, along with the methods that bodily functions use to counteract and potentially kill invading microorganisms. Woven into this discussion are several specific sites that Zimmer visited during his writing of Parasite Rex' and the scientists he worked with to understand different biosystems and all the parasites that live within them, including human sleeping sickness infections in Sudan from the tsetse fly, the parasites of frogs in Costa Rica, primarily showcased by filarial worms that infect humans and a variety of species, and the USDA National Parasite Collection based out of Maryland.
The final chapters focus on an overall effect parasites have had on the evolution of life and the theory that it is due to parasitic infection that sexual reproduction evolved to become dominant, in contrast to previous asexual reproduction methods, due to the increased genetic variety and thus potential parasitic resistance that this would confer. This research was showcased by W. D. Hamilton and his theories on the evolution of sex, along with the Red Queen hypothesis and the idea of an evolutionary arms race between parasites and their hosts. Zimmer then discusses a final time the wide variety of parasites that evolved to have humans as their primary hosts and our attempts through scientific advancement to eradicate them. The closing chapter considers the positive benefits of parasites and how humans have used them to improve agriculture and medical technology, but also how ill-considered usage of parasites could also destroy various habitats by having them act as invasive species. In the end, Zimmer ponders whether humanity counts as a parasite on the planet and what the effects of this relationship could be.