The cloning of the ob gene and its gene product leptin has led to the elucidation of a robust physiological system that maintains fat stores at a relatively constant level. Leptin is a peptide hormone secreted by adipose tissue in proportion to its mass. Recessive mutations in the leptin gene are associated with massive obesity in mice and some humans establishing a genetic basis for obesity. Leptin circulates in blood and acts on the brain to regulate food intake and energy expenditure. When fat mass falls, plasma leptin levels fall stimulating appetite and suppressing energy expenditure until fat mass is restored. When fat mass increases, leptin levels increase, suppressing appetite until weight is lost. This system maintains homeostatic control of adipose tissue mass. The cloning of the ob gene and hormone leptin has led to several new insights. The identification of leptin has uncovered a new endocrine system regulating body weight. This system provides a means by which changes in nutritional state regulate other physiological systems. There are a number of leptin deficiency syndromes that are treatable with leptin replacement. The majority of obese subjects are leptin resistant establishing that obesity is the result of hormone resistance. Leptin treatment results in weight loss in a subset of obese patients and can also synergize with other anti-obesity agents. Leptin also has metabolic effects that are independent of its effects on food intake and body weight, findings which provide insights into the mechanisms by which the CNS controls fat and glucose metabolism. Leptin provides an entry point for studying a complex human behavior. Finally, there is a powerful biological basis for obesity, a fact that is (correctly) changing public perception about this medical condition.