Leptin is a hormone produced by adipose tissue that is needed to regulate appetite and energy balance. Leptin (LEP) and leptin receptor (LEPR) deficiencies are rare genetic disorders with an autosomal recessive inheritance pattern. The main clinical phenotype consists of hyperphagia and early-onset obesity, often accompanied by endocrinopathies such as hypogonadotropic hypogonadism, growth hormone deficiency, and central hypothyroidism. Both leptin and leptin receptor deficiency negatively impact quality of life, morbidity and mortality. Personalized treatment options, aimed on the pathophysiology of the disorders, are available in the form of recombinant leptin for leptin deficiency and MC4R agonists for leptin receptor deficiency.