Pyrogenic tolerance has been recognized for many years in a variety of species although the mechanisms that are responsible for its development are not well understood. The development of pyrogenic tolerance is associated with the stepwise diminution of pathophysiological and behavioral responses induced by exogenous pyrogens, such as fever, reduction in food and water inteke. Several studies either in vivo or ex vivo have indicated the role of various proinflammatory cytokines in the development of pyrogenic tolerance. Most of these studies have indicated that pyrogenic tolerance is associated with down-regulation of cytokine production as well as their biological activity The mechanisms responsible for down-regulation of cytokine production during development of pyrogenic tolerance are unclear. Since glucocorticoids are required for induction of tolerance, it has been postulated that well known glucocorticoids-dependent negative feedback on the production and biological activity of cytokines may play an important role in development of pyrogenic tolerance. We can not, however, rule out possibility that other mechanisms may participate directly or indirectly in a suppression of cytokines response due to repeated exogenous pyrogen challenge. Either the enhanced uptake of exogenous pyrogens by the hepatic Kupffer cells or the desensitization to exogenous pyrogens by the loss of binding sites, have been proposed as an additional mechanisms which may participate in exogenous pyrogen hyporesponsiveness.