Abstract: Proopiomelanocortin (POMC) is expressed in the arcuate nucleus of the hypothalamus (ARC) and the commissural nucleus of the solitary tract (cNTS). Post‐translational processing of POMC produces two melanocortin receptor ligands, α‐ and γ‐melanocyte‐stimulating hormone (MSH). Two melanocortin receptors (MC3R, MC4R) are expressed in brain regions receiving projections of POMC fibers, most of which also receive projections from a population of ARC neurons that co‐express neuropeptide Y (NPY) and the MC3R/MC4R antagonist agouti‐related peptide (AgRP). MC4R haploinsufficient humans and MC4R knockout (MC4RKO) mice exhibit increased adiposity and linear growth. MC4RKO mice exhibit hyperleptinemia and hyperinsulinemia and sometimes, but not always, develop type 2 diabetes (T2D). Individually housed MC4RKO mice fed low‐fat diets are not hyperphagic when food intake is corrected for lean mass, whereas hyperphagia is observed after the introduction of diets with increased fat content. POMC knockout (POMCKO) mice are similar in that the severity of hyperphagia increases with the introduction of high‐fat diets. By contrast, targeted deletion of the MC3R in the mouse results in increased adiposity despite the absence of hyperphagia. MC3RKO mice also exhibit reduced linear growth and lean mass; while MC3RKO mice are hyperleptinemic and hyperinsulinemic, the development of T2D has not been reported. The MC4R, but not the MC3R, is required for the stimulation of energy expenditure in response to melanocortin agonists and voluntary hyperphagia. Evidence for altered physical activity has also been reported for both knockout models. Analysis of MC4RKO mice indicates that this receptor is involved in rapidly coordinating energy consumption with energy expenditure through diet‐induced thermogenesis and activity.