Accumulation of fat in the tissues results from the balance between energy intake and expenditure. The thyroid hormones have long been known to be the main regulators of basal metabolism through its stimulation of oxygen consumption in cells. The discovery of brown adipose tissue (BAT) and its unique activity of heat production and dissipation through the action of uncoupling protein-1 (UCP1) during cold stress, showed the relevance of this tissue for energy expenditure in lower mammals. UCP1 is only expressed in BAT through the synergistic action of norepinephrine (NE) and thyroid hormones in animals exposed to cold and to a lesser degree after meals. The uncoupling protein-2 (UCP2) is found in many tissues and exerts dual effects: it protects cells function from damage caused by reactive oxygen species (ROS). On the other hand, the uncoupling induced by UCP2 in mitochondria of pancreatic beta cells decreases ATP synthesis and impairs insulin secretion in response to glucose. Hyperlipidemia also prevents insulin secretion through a similar pathway, leading to hyperglycemia. The uncoupling protein-3 is found mostly in skeletal muscle and BAT and its absence did not alter heat production or body temperature. This protein would export fatty acids ouside the mitochondrial matrix for combustion in tissues where fat is the main fuel. In humans, the uncoupling proteins may not play a leading role in energy regulation. However, intensive studies on these and other factors influencing energy expenditure, appetite and glucose metabolism are taken place worldwide and may soon provide more clues on the mechanisms regulating energy balance and their use in the prevention or treatment of human obesity and diabetes type 2.