Thermogenesis (adaptive increases in heat production) can develop in response to low environmental temperature, alterations in the amount or composition of the diet, and pathogenic stimuli, such as infection, injury, and inflammation. Thermogenic responses to each of these stimuli appear to be mediated by activation of the sympathetic nervous system and, at least in experimental animals, by heat production in brown fat. Thermogenesis is under the direct control by the central nervous system (CNS), particularly by specific regions of the hypothalamus. Serotonergic pathways have been directly implicated in the central control of most forms of thermogenesis, and indirect evidence suggests involvement of adrenergic and cholinergic mechanisms. Numerous peptides have been shown to induce increases on metabolic rate when injected into the brains of experimental animals; of these, corticotrophin-releasing factor (CRF) has been the most extensively studied. CRF appears to mediate thermogenic responses to serotonergic agonists, injury, and cytokines, and may be involved in impaired thermogenic responses in certain genetically obese rodents. Cytokines, particularly interleukin-1 (IL-1) and IL-6, act as endogenous pyrogens in the brain and stimulate thermogenesis via synthesis of prostaglandins and CRF. Peptides such as lipocortin-1, arginine vasopressin, and alpha MSH potently inhibit central effects of cytokines. Pharmacological modification of thermogenesis may be clinically beneficial in treating conditions such as obesity, cachexia, and fever.