The discovery of novel uncoupling proteins (UCP2 and UCP3) over 10 years ago heralded a new era of research in mitochondrial uncoupling in a diverse range of tissues. Despite the research vigor, debate stills surrounds the exact function of these uncoupling proteins. For example, the level of uncoupling, the mechanism and mode of action are all under-appreciated at this point in time. Our recent work has used genetic mouse models to focus on the physiological relevance of UCP2. We have used these mouse models to better appreciate the role UCP2 in human health and disease. In this review we focus on new research showing that UCP2 promotes longevity by shifting a given cell towards fatty acid fuel utilization. This metabolic hypothesis underlying UCP2-dependent longevity suggests that UCP2 is critically positioned to maintain fatty acid oxidation and restrict subsequent oxidative damage allowing sustained mitochondrial oxidative capacity and mitochondrial biogenesis. These mechanisms converge within the cell to boost cell function and metabolism and the net result promotes healthy aging and increased lifespan. Finally, UCP2 is a useful dietary and therapeutic target to promote lifespan and is an important mitochondrial protein connecting longevity to metabolism.