The leptin-melanocortin pathway is a critical neuroendocrine system involved in regulating energy balance, appetite, and body weight. The main features of non-syndromic leptin-melanocortin pathway disorders are hyperphagia and severe, early-onset obesity. Intellectual disability or congenital anomalies are generally not present. The most common non-syndromic genetic obesity disorder is heterozygous MC4R deficiency. Other well-known rare autosomal recessive obesity disorders result from pathogenic biallelic variants in LEP, LEPR, POMC and PCSK1. Some of these disorders are also associated with hormonal imbalances, for example in the production of pituitary hormones such as adrenocorticotropic hormone (ACTH), gonadotropins, or growth hormone. Identifying patients with non-syndromic leptin-melanocortin pathway disorders is essential for personalized treatment options. Several of these disorders can be treated with targeted drug therapy.