Uncoupling protein-3 (UCP3) is selectively expressed in skeletal muscle of rodents and humans, and in brown adipose tissue (BAT) of rodents. C2C12 myoblast transfection with UCP3 induced a decrease in mitochondrial membrane potential suggesting that UCP3 behaves as an uncoupler of oxidative phosphorylations. Cold-exposure, food restriction and fasting affect UCP3 mRNA expression differently in BAT, compared to muscle. The effects induced by cold-exposure and fasting in BAT, and by fasting in muscle, might be explained by changes in intracellular free fatty acids (FFA). A single bout of exercise or endurance training, respectively, increases or decreases muscle UCP3 expression. The effects of PPARgamma agonists and leptin on BAT and muscle UCP3 mRNA expression are also discussed. Hypotheses to explain the effects of these modulations are presented.