MCs are peptide hormones involved in the regulation of an increasing list of processes: pigmentation, cortisol production, food intake, energy and metabolism homeostasis, sexual behaviour, exocrine gland function and inflammation. One of the most important players of this system is αMSH, a neuroimmunomodulatory tri-decapeptide derived from POMC; while it has been demonstrated in melanocytes, monocytes, B-cells, NK, a subset of cytotoxic T-cells, epithelial cells and in keratinocytes, the skin is one of the most relevant extrapituitary sources of αMSH expression and secretion. The key role of MCs in skin/hair colour regulation has been widely figured out in man and animal models. UV-light induces the production of MCs; additionally other skins produced cytokines and parakrine factors (CRH, IL-1, TNF-α, and TGF-β) regulate MC production and MC-1R activity. Moreover MCs and their autoAbs are involved in grooming behaviour, antipyretic and antinflammatory responses, learning, reproductive function, appetite regulation, eating disorders, energy homeostasis, ethanol consumption and violent conduct. A strong and not well understood association between skin malignancies and the CRH-POMC axis has been shown. The MCs bind to five MC-Rs. Each MC-R binds several MCs with the exception of MC-2R, strongly selective for ACTH, unlike the expression of MC-R which is tissue specific, MC-5R being the most widespread. The discovery of the influence of MC in the inflammation modulation, food intake behaviour, lipid metabolism, sex activities, neoplasm development and autoimmune diseases is attracting more and more attention to define new therapeutic strategies and drugs like αMSH and the related tripeptide KPV and K(D)PT.