Melanocortin peptides, derived from pro-opiomelanocortin (POMC), appear to play a significant role in appetite and body weight regulation. Expression of the Pomc gene in the central nervous system results in the production of melanocortin peptides, which bind to the melanocortin-4 receptor (MC4-R) and inhibit food intake. MC4-R knockout mice exhibit adult-onset obesity, whereas MC4-R agonists suppress food intake in several models of obesity. Recently, Pomc knockout mice were generated and shown to develop hyperphagia and obesity with a time-course and severity comparable to MC4-R knockout mice, whereas daily administration of a stable alpha-melanocyte stimulating hormone analogue reversed this effect. These data clearly implicate POMC peptides and melanocortin receptors in the pathophysiology of obesity and provide important new tools for their development as therapeutic targets in obesity.