The melanocortins, alpha-, beta- and -melanocyte-stimulating hormones (MSHs), are peptides derived from a precursor protein POMC. The MSH peptides bind to a family of five Gs-coupled seven transmembrane recptors (MC1-5) and play important roles in energy balance, reproductive function, pigmentation and inflammation. The activity of the melanocortins is modulated by endogenous antagonist proteins, agouti and agouti-related protein (AGRP). MC4 is expressed primarily in the CNS and appears to play a prominent role in energy homeostasis. The hypothalamus, which is a major central site for control of feeding behavior, prominently expresses MC4. Targeted deletion of MC4 in mice and naturally occurring mutations in MC4 in humans result in obese phenotypes. In addition, blockade of MC4 function by antagonists and targeted deletion of the gene in mice reverses melanocortin agonist-induced inhibition of food intake and promotes weight gain in uremia and cancer-induced cachexia.