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Summary by: Paul Young The febrile response to infection occurs in most animals and is regulated by a common biochemical mechanism involving prostaglandin E2. This common mechanism suggests that the response may have evolved in a common ancestor more than 350 million years ago. As the febrile response comes at a significant metabolic cost, its persistence across a broad range of species provides circumstantial evidence that the response has some evolutionary advantage. Furthermore, it logically follows that the components of the immune system would have evolved to function optimally in the physiological febrile range. There are a number of historical examples of dramatic responses to treatment with therapeutic hyperthermia in some infectious diseases, including neurosyphilis and malaria. The relevance of these historical examples to the modern era is unclear. Furthermore, arguments based on the evolutionary importance of the febrile response do not necessarily apply to critically ill patients who are, by