The discovery of leptin changed the view of adipose tissue from that of a passive vessel that stores fat to that of a dynamic endocrine organ that actively regulates behaviour and metabolism. Secreted by adipose tissue, leptin functions as an afferent signal in a negative feedback loop, acting primarily on neurons in the hypothalamus and regulating feeding and many other functions. The leptin endocrine system serves a critical evolutionary function by maintaining the relative constancy of adipose tissue mass, thereby protecting individuals from the risks associated with being too thin (starvation and infertility) or too obese (predation). In this Review, the biology of leptin is summarized, and a conceptual framework is established for studying the pathogenesis of obesity, which, analogously to diabetes, can result from either leptin hyposecretion or leptin resistance. Herein, these two states are distinguished with the terms ‘type 1 obesity’ and ‘type 2 obesity’: type 1 obesity describes a subset of obese individuals with low endogenous plasma leptin levels who respond to leptin therapy, whereas type 2 obesity describes most obese individuals, who are leptin resistant but might respond to leptin therapy in combination with other drugs, such as leptin sensitizers.