Significant progress in our understanding of the mechanisms of weight homeostasis has been made by studying the many genetic mouse models of obesity. Positional cloning in the obese mouse led to the discovery of leptin as a feedback messenger indicating the adequacy of peripheral energy stores. This was the first in a series of important advances in this field. Shortly after this discovery, two research laboratories presented evidence for the role of hypothalamic pro-opiomelanocortinergic (POMC) neurons as important mediators in the regulation of feeding behavior, insulin levels and, ultimately, body weight. One of these mouse obesity models, the lethal yellow mouse, constitutively overexpresses the agouti protein, an endogenous antagonist of both the melanocortin 1 (MC1) and melanocortin 4 (MC4) receptors. A second mouse obesity model was created by knocking out the MC4 receptor. Investigations using both the autosomal dominant lethal yellow mouse and MC4 receptor knockout mouse have provided clear evidence for the role of hypothalamic POMC neurons and the MC4 receptor in the regulation of weight homeostasis in the rodent. Furthermore, the recent discovery of agouti-related protein (AGRP), an agouti-like peptide naturally found in the hypothalamus, provides further evidence for the importance of POMC neurons in the regulation of weight. Although the significance of central POMC and AGRP in the rodent is apparent, the role of POMC neurons in the regulation of weight and feeding behavior in humans is only now being appreciated.