The recent discovery of the contribution of proopiomelanocortin (POMC)-derived peptides to the regulation of energy homeostasis and exocrine gland secretion in mice aroused new interest in the complex function of the endocrine POMC network. In addition, the first mutations in the gene encoding POMC have been identified in two patients affected by adrenal insufficiency, early onset severe obesity and red hair pigmentation. Therefore, the focus of this brief review will be the detailed discussion of the implications of these new findings in the physiology of the human POMC ligand-receptor system.