Obesity has become one of the most significant public health problems facing the world today. However, the pathogenesis of obesity is multifactorial and involves the interaction of genetic and environmental factors. There is a pressing need to better understand the biochemical pathways that control energy intake and expenditure. In the last few years, a number of important signalling molecules have been identified that play important roles in obesity. One family of these molecules is the melanocortin system, which consists of several components: (1) melanocortin peptides; (2) the five seven-transmembrane G-protein coupled melanocortin receptors (MCRs); (3) the endogenous MCR antagonists, agouti and agouti-related protein; (4) the endogenous melanocortin mediators, mahogany, and syndecan. This system plays a key role in the central nervous system control of feeding behaviour and energy expenditure. This article will provide an overview of the anatomy, physiology, and molecular biology of the melanocortin system, and recent developments in our understanding of this system in obesity.