Commensurate with the last decade's increasing prevalence of obesity is the number of breakthroughs in the physiology of energy regulation. Primary of these is the role played by the CNS melanocortin 3 and 4 receptors (MC3/4R). The MC3/4 ligand, alpha-melanocyte stimulating hormone, is a primary anti-obesity target due to its anorectic and catabolic actions. A level of complexity is introduced by agouti related peptide, an endogenous antagonist at the MC3/4R that exerts orexigenic and anabolic functions. Here we evidence the utility of the MC system to treat obesity by reviewing the long-lasting changes in food intake, selection of fat, propensity to develop or resist obesity, and ability to burn energy that occurs in knockout mice, and in animals administered endogenous and synthetic MC ligands. Further evidence is conferred by the high frequency of MC4R mutations among human monogenetic obesities. As a downstream regulator of leptin and insulin, and integrator of opioid and dopamine functions, the MC system is positioned to override leptin and insulin resistance, as well as addictive-like regard of food that contributes to obesity. We review advances in identification of vital structural elements in MC binding, autoregulation and inverse agonist theories, the development of novel potent and selective non-peptide ligands, and non-traditional biochemical approaches to achieve pseudoagonist effects. Finally we review the status of small molecule ligands, outcomes of the clinical studies testing MC compounds, and suggest requirements of the optimal anti-obesity drug, novel delivery strategies, and the adjunct use of fatty acid oxidation elements to treat obesity.