Melanocortin-4 receptor deficiency (MC4R deficiency) is a genetic disorder associated with early-onset obesity and hyperphagia. The most severe form is caused by biallelic (homozygous or compound heterozygous) variants. However, a monoallelic (heterozygous) pathogenic variant in MC4R can also lead to a phenotype of childhood-onset obesity and hyperphagia. This is the most common type of genetic obesity disorder. MC4R deficiency leads to obesity because decreased MC4R signalling results in impaired satiety and decreased energy expenditure. This chapter highlights the pathophysiology and clinical presentation of MC4R deficiency, encompassing both recessive and dominant forms, and shows the developments in therapy options for MC4R deficiency (Fig. 1).