Physical activity influences energy metabolism in human subjects by increasing activity-induced energy expenditure and resting metabolic rate for several hours after exercise. On the other hand, physical activity increases mechanical energy efficiency, suggesting that trained subjects would need less energy for daily activities. The underlying mechanism by which physical activity influences energy metabolism is largely unknown. The skeletal muscle-specific homologue of uncoupling protein (UCP) 1, UCP3, could possibly play a major role in energy expenditure. UCP3 is, like UCP1, able to uncouple respiration from ATP production. A strong link or association between the UCP3 gene and energy metabolism was found. Furthermore, UCP3 mRNA expression is related to sleeping metabolic rate, and thyroid hormone, a powerful stimulator of energy expenditure, up regulates UCP3. Finally, mice overexpressing UCP3 are hyperphagic but lean. These findings indicated that UCP3 is related to energy metabolism and that UCP3 could have a role in the effect of physical activity on energy expenditure. Thus, acute exercise up regulates UCP3, whereas endurance training results in the down-regulation of UCP3 protein content. Only a minimal amount of physical activity is needed for down-regulation of UCP3. Moreover, there is very strong evidence that UCP3 is negatively related to mechanical energy efficiency, suggesting that the down-regulation of UCP3 with training increases mechanical energy efficiency. Taken together, although the exact function of UCP3 is still unknown, exercise and training studies clearly show that under certain circumstances UCP3 is strongly related to human energy metabolism, possibly as a secondary effect of its (yet) unknown primary function.