The physiological function of the human uncoupling protein 3 UCP3, which was discovered in 1997, is unknown. Here we evaluate the available data on human UCP3 expression and show that UCP3 is up-regulated in situations where fatty acid delivery to the mitochondria exceeds oxidative capacity, whereas down-regulation of UCP3 is observed when oxidative capacity is enhanced. With a surplus of fatty acid delivery, accumulation of nonesterified fatty acids in the cytoplasm is likely to occur. Although the inner mitochondrial membrane provides a barrier for nonesterified fatty acids, neutral nonesterified fatty acids can partition into the phospholipid bilayer and flip-flop to the other side of the membrane, where they can be released into the mitochondrial matrix. Due to pH differences, these nonesterified fatty acids will be protonated. Because fatty acid anions can neither be metabolized inside the matrix or cross the inner mitochondrial membrane, accumulation of nonesterified fatty acids inside the matrix might occur. Therefore, we postulate that UCP3 is required for the outward translocation of fatty acids from the mitochondrial matrix. In this way, UCP3 is involved in the protection of mitochondria against accumulation of nonesterified fatty acids inside the mitochondrial matrix.