Leptin is an adipocyte hormone that signals nutritional status to the central nervous system (CNS) and peripheral organs. Leptin is also synthetized in the placenta and in gastrointestinal tract, although its role in these tissues is not yet clear. Circulating concentrations of leptin exhibit pulsatility and circadian rhythmicity. The levels of plasma leptin vary directly with body mass index and percentage body fat, and leptin contributes to the regulation of body weight. Leptin plasma concentrations are also influenced by metabolic hormones, sex, and body energy requirements. Defects in the leptin signaling pathway result in obesity in animal models. Only a few obese humans have been identified with mutations in the leptin gene or in the leptin receptor; however, most cases of obesity in humans are associated with high leptin levels. Thus, in humans obesity may represent a state of leptin resistance. Minute-to-minute fluctuations in peripheral leptin concentrations influence the activity of the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes, indicating that leptin may be a modulator of reproduction, stress-related endocrine function, and behavior. This suggests potential roles for leptin or its antagonists in the diagnosis, pathophysiology and treatment of several human diseases.