Based on observations that fever is suppressed under several physiological circumstances the existence of endogenous antipyretically active molecules has been postulated. A large number of experimental and some clinical studies provided evidence that the neuropeptides arginine vasopressin (AVP), α- and γ-melanocyte stimulating hormones (α-MSH, γ-MSH) and adrenocorticotropic hormone (ACTH) as well as glucocorticoids are capable to antagonize febrile responses to pyrogens. Endogenous antipyresis is mediated by actions of these molecules within the central nervous system or, at least in some cases, by peripheral effects. Brain sites where endogenous antipyresis is activated include the septal area of the limbic system and the anterior hypothalamus. The precise neuronal mechanisms of how the aforementioned endogenous mediators cause a limitation or even suppression of fever are not known. There is, however, evidence that endogenous antipyretics cancel changes in neuronal activities which have been induced by endogenous pyrogens such as cytokines and prostaglandins. At the level of the hypothalamic controller of thermoregulation antipyretic peptides seem to cause a reversion of the pyrogen-induced upward shift of the threshold body core temperature for activation of metabolic heat production. Such a change in thermoregulatory characteristics is compatible with a limitation of fever in strength and duration.