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From the early 1920s until the advent of penicillin in the mid 1940s, a clinical course of malaria was the only effective treatment of general paresis, a common manifestation of tertiary syphilis that was nearly always fatal. For a number of reasons, Plasmodium vivax became the parasite species most often employed for what became known as malariotherapy. This provided an opportunity, probably unique in the annals of medicine, to observe and investigate the biology, immunology and clinical evolution of a dangerous human pathogen in its natural host. There is little doubt that the lessons learned from these studies influenced the malaria research and control agendas. It is equally true that over the last 40 years, the insights afforded by malariotherapy have remained largely undisturbed on the dusty shelves of institutional libraries. In this chapter, we broadly review the published data derived from malariotherapy, and discuss its relevance to current challenges of P. vivax epidemiology, immunology and pathology., (Copyright © 2013 Elsevier Ltd. All rights reserved.)