The adipocyte-secreted hormone, leptin, and its hypothalamic target, the melanocortin system, play a pivotal role in body weight regulation. The melanocortin-4 receptor (MC4R), predominantly expressed in the hypothalamus, is crucial and its activation leads to a decrease in food intake. The MC4R mutations described in human obesity studies since 1998 are responsible for an oligogenic form of obesity lying somewhere between the rare forms of monogenic obesity (mutations in the leptin receptor, leptin, proopiomelanocortin and proconvertase 1 genes) and polygenic obesity. Their frequency is 2-3% in obese populations, with up to 90 different mutations (insertion, deletion and missense) described. They demonstrate autosomal dominant inheritance and vary in severity of the obesity phenotype within families, suggesting the influence of environmental and/or genetic factors. Phenotype expression in MC4R mutation carriers has not been established, except for early-onset obesity and, recently discovered, a decrease in bone resorption parameters. The functional consequences of these mutations are multiple (intracellular retention and impairment of the constitutive activity of receptors and response to ligands) and demonstrate a correlation between genotype and phenotype. In the future, MC4R agonists currently in development could play a specific role in the treatment of MC4R deficiency-linked obesity.