Recent advances indicate that a robust physiologic system acts to maintain relative constancy of weight in mammals. A key component of this system is leptin. Leptin is an adipocyte hormone that functions as the afferent signal in a negative feedback loop regulating body weight. In addition, leptin functions as a key link between nutrition and the function of most, if not all other physiologic systems. When at their set point, individuals produce a given amount of leptin and in turn maintain a state of energy balance. Weight gain results in an increased plasma leptin level, which elicits a biologic response characterized in part by a state of negative energy balance. Weight loss among both lean and obese subjects results in decreased plasma levels of leptin, which lead to a state of positive energy balance and a number of other physiologic responses. In humans, both the intrinsic sensitivity to leptin and its rate of production vary and both appear to contribute to differences in weight. Further studies of leptin, its receptor, and the molecular components of this system are likely to have a major impact on our understanding of obesity and the interplay between nutrition and physiology.