alpha-MSH, has numerous actions in the skin and by activating the MC1 receptor (MC1-R) on melanocytes it stimulates melanogenesis. Rather than producing large increase in melanin production alpha-MSH acts specifically to stimulate eumelanin synthesis. Although this could be important in determining skin color and tanning there is debate as to the pigmentary significance of alpha-MSH in humans. Circulating levels of alpha-MSH are negligible and although it is produced in the skin by different cell types, including melanocytes, the major skin form is desacetyl alpha-MSH, and this is a weak agonist at MC1-R. Certain ACTH peptides, notably ACTH1-17, are more potent agonists at the MC1-R and, since their skin concentrations exceed those of alpha-MSH, they could serve as natural ligands at this receptor and regulate pigmentary responses in humans. Activation of MC1-R does, however, produce other responses in human melanocytes. Thus, alpha-MSH stimulates melanocyte dendricity and attachment to extracellular matrix proteins. It also protects melanocytes from the damaging effects of oxidative stress, and regulates their production of NO by modulating the induction of iNOS--as it does within macrophages. alpha-MSH clearly affects various aspects of melanocyte behavior and its melanogenic effects could be the consequence of a more fundamental role in the melanocyte. The precise nature of this role is unclear, but it could be part of a generic role that alpha-MSH and other POMC peptides have in skin homeostasis.