Large inter-individual differences in cold-induced (non-shivering) and diet-induced adaptive thermogenesis exist in animals and humans. These differences in energy expenditure can have a large impact on long-term energy balance and thus body weight (when other factors remain stable). Therefore, the level of adaptive thermogenesis might relate to the susceptibility to obesity; efforts to increase adaptive thermogenesis might be used to treat obesity. In small mammals, the main process involved is mitochondrial uncoupling in brown adipose tissue (BAT), which is regulated by the sympathetic nervous system. For a long time, it was assumed that mitochondrial uncoupling is not a major physiological contributor to adaptive thermogenesis in adult humans. However, several studies conducted in recent years suggest that mitochondrial uncoupling in BAT and skeletal muscle tissue in adult humans can be physiologically significant. Other mechanisms besides mitochondrial uncoupling that might be involved are futile calcium cycling, protein turnover and substrate cycling. In conjunction with recent advances on signal transduction studies, this knowledge makes manipulation of adaptive thermogenesis a more realistic option and thus a pharmacologically interesting target to treat obesity.