It is now recognized that appropriate regulation of energy intake and energy expenditure, and thus maintenance of body weight, relies on complex hypothalamic neurocircuitry. The importance of key neuropeptide systems identified in rodents is now being established in humans. Notably, mutations in the melanocortin MC4 receptor are found in as many as 4% of the morbidly obese. Intranasal administration of a melanocortin fragment known to activate the MC4 receptor decreases adiposity in humans. Since the discovery of leptin, attention has also focused on peripheral signals that regulate food intake and energy expenditure either directly or via feedback on hypothalamic circuits. Notable new discoveries in this area include the gastric hormone ghrelin and circulating melanocortins.