The concept that changes in adaptive thermogenesis can play an important role in the regulation of energy balance has been much debated. There is strong evidence from animal studies in support of such a proposition, particularly from work on rats consuming a cafeteria diet (diet-induced thermogenesis) and from genetically obese rodents (ob/ob and db/db mice and fa/fa rats). The extent to which thermogenesis is a component of energy balance in humans is still unclear, however, but there is little doubt that any role is at best minor. Several mechanisms for adaptive thermogenesis have been considered, but the only one for which there is compelling evidence is that associated with brown adipose tissue. Brown fat is specialised for heat generation through a regulated dissipation of the mitochondrial proton gradient. This is effected by a 32 000 molecular weight uncoupling protein (now termed uncoupling protein-1, or UCP1) located in the inner mitochondrial membrane. UCP1, which exists in active and inactive forms, is unique to brown fat and as such differentiates the two forms of adipose tissue (brown and white); it also appears to be restricted to mammals. A family of mammalian uncoupling proteins has now been identified – UCP1, UCP2, UPC3, BMCP1 (and perhaps UCP4) – with homologues in birds and plants. UCP2 has a wide tissue distribution, but is found particularly in white adipose tissue and cells of the immune system, while UCP3 is primarily expressed in skeletal muscle. Although these proteins were initially thought to act as uncouplers in a manner analogous to UCP1, it is increasingly clear that this is not the case. UCP2 and UCP3 may in practice be involved in lipid oxidation or play a role in anti-oxidant defence. A role for UCP1 and for brown adipose tissue as a locus for adaptive thermogenesis in relation to energy balance, as well as in thermoregulation, in rodents is well established. However, the extent to which brown fat thermogenesis normally occurs in adult humans remains problematic. Nevertheless, UCP1 is present in certain adipose tissue depots throughout life and increased levels (indicating activation of brown fat) are evident in patients with pheochromocytoma.