Although vital to life, mitochondria are also the major source of ROS production, which may have unwanted detrimental effects on DNA, RNA and protein structures Therefore, mitochondria must exhibit well-developed mechanisms to regulate its ROS production. One such mechanism might be mild uncoupling of the mitochondrial respiratory chain, thereby lowering the proton gradient across the inner mitochondrial membrane and directly lowering ROS production. Mitochondrial uncoupling proteins have been shown to possess mild uncoupling activity and may therefore be important regulator of mitochondrial ROS production. The skeletal muscle isoform of the uncoupling protein family, UCP3, seems to be specifically active under conditions of high fatty acid availability. Although the exact function of UCP3 is not yet unravelled, UCP3 is activated by lipid peroxides and suggested to export fatty acid anions and/or peroxides from the mitochondrial matrix, thereby specifically protecting fatty acids from ROS-induced oxidative damage. Protein levels of UCP3 are reduced with aging and in the (pre)-diabetic state, both conditions characterized by increased levels of oxidative damage to lipids and proteins and reduced mitochondrial function. Whether UCP3 is causally related to mitochondrial dysfunction and is essential in the prevention and treatment of lipid-induced mitochondrial dysfunction requires further study.