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Uncoupling proteins (UCPs) are mitochondrial proteins able to dissipate the proton gradient of the inner mitochondrial membrane when activated. This decreases ATP-generation through oxidation of fuels and may theoretically decrease energy expenditure leading to obesity. Evidence from Ucp(−/−) mice revealed a role of UCP2 in the pancreatic β-cell, because β-cells without UCP2 had increased glucose-stimulated insulin secretion. Thus, from being a candidate gene for obesity UCP2 became a valid candidate gene for type 2 diabetes mellitus. This prompted a series of studies of the human UCP2 and UCP3 genes with respect to obesity and diabetes. Of special interest was a promoter variant of UCP2 situated 866bp upstream of transcription initiation (−866G>A, rs659366). This variant changes promoter activity and has been associated with obesity and/or type 2 diabetes in several, although not all, studies. The aim of the current paper is to summarize current evidence of association of UCP2 genetic variation with obesity and type 2 diabetes, with focus on the −866G>A polymorphism.