Infections and injury are often accompanied by the production of large quantities of proinflammatory mediators such as cytokines and eicosanoids. These substances have been shown to efficiently activate the hypothalamic-pituitary-adrenocortical (HPA) system. The glucocorticoid hormones secreted from the adrenal cortex seem to be crucial for survival because they have an inhibitory influence on inflammatory processes, which, if uncontrolled, may become toxic for the host. Furthermore, these steroid hormones are known to support thermogenesis by inducing or repressing key enzymes of carbohydrate, lipid, and protein metabolism, and thus may also facilitate energy mobilization during fever, which usually accompanies infectious diseases. Finally, a number of studies suggest that glucocorticoids attenuate debilitating symptoms of inflammatory mediators, such as sleepiness, loss of appetite, and suppression of reproductive functions. One can assume that glucocorticoids exert similar behavioral effects during inflammatory conditions, which are seen in infectious diseases. Corticotropin-releasing hormone (CRH), the major hypothalamic component of the HPA system, is a putative mediator of the central effects of cytokines and autacoids because it inhibits growth, reproduction, and food intake. In contrast, CRH decreases sleep duration. Vasopressin, another hypothalamic peptide of the HPA system, counteracts fever and sickness behavior and is thought to support recovery from inflammatory diseases. Apparently, a well-balanced, concerted action of proinflammatory mediators, glucocorticoids, and hypothalamic peptide hormones provides not only an efficient principle for combating microorganisms and support of tissue repair but also for self-protection of the host during the stress of inflammation. Therefore, an impairment of the HPA system under inflammatory conditions often has severe pathological consequences, for example, in patients suffering from Addision's disease and arthritis.