▪ Abstract Animals have developed highly adaptive and redundant mechanisms to maintain energy balance by matching caloric intake to caloric expenditure. Recent evidence has pointed to a variety of peripheral signals that inform specific central nervous system (CNS) circuits about the status of peripheral energy stores as critical to the maintenance of energy balance. A critical component of these CNS circuits is the melanocortin system. Regulation of signaling by melanocortin 3 and melanocortin 4 receptors in the CNS is controlled via neuronal cell bodies in the arcuate nucleus of the hypothalamus that synthesize melanocortin receptor agonists such as alpha-melanocyte-stimulating hormone (α-MSH) or antagonists such as agouti-related protein (AgRP). The activity of these two populations of neurons is reciprocally regulated by a number of peripheral and central systems that influence energy balance. Further, increased melanocortin signaling via pharmacological or genetic means in the CNS causes potent reductions in food intake and weight loss. Decreased melanocortin signaling via pharmacological or genetic means results in increased food intake and weight gain. Reviewed here is the wide range of evidence that points to the melanocortin system as a critical node in the diverse neurocircuitry that regulates food intake and body weight.