The importance of an upper limit of the febrile response has been recognized since the time of Hippocrates. Although the precise temperature defining this limit varies according to the site at which body temperature is measured, human core temperature is almost never permitted to rise above 41 degrees C-42 degrees C during fever. There are compelling physiological reasons for such an upper limit of regulated body temperature. The mechanisms by which the limit is maintained are most likely complex and involve special properties of thermoregulatory neurons themselves, circulating endogenous antipyretics (such as arginine vasopressin and alpha-melanocyte-stimulating hormone), and soluble receptors for the (pyrogenic) cytokine mediators of the febrile response.