Genetic studies in humans provide a method to test hypotheses about the biological roles of specific genes. So far, ten published papers have chosen to examine the hypothesis that uncoupling protein-2 (UCP2) and/or UCP3 influence energy expenditure and/or body fat accumulation. These genes were chosen because they are candidate energy expenditure genes, based on their homology to UCP1. Studies of UCP2 and UCP3 are intrinsically intertwined because the two genes are separated by only 6000 base pairs on human chromosome 11. Linkage studies in families have suggested that UCP2 and/or UCP3, or a closely linked gene, may influence resting metabolic rate (RMR) Some association studies using a 3' untranslated region insertion/deletion variant of UCP2 have produced statistically positive evidence for association with body mass index (BMI) and RMR. In contrast, association studies of UCP2 using an Ala to Val variant at amino acid 55 have produced negative results. Positive results have also been reported for association of a UCP3 splice variant with respiratory quotient in African Americans. In addition, no studies have reported linkage or association of UCP2 or UCP3 with diabetes. Overall, the results suggest that some variants of UCP2 and UCP3 may be associated with obesity traits in some populations. The UCPs, to date, show positive results in associations with obesity traits but not with diabetes traits. Further work will be needed to settle the role of UCP2 and UCP3 alleles in human body weight regulation.