Over the years there has been much debate as to whether alpha-MSH has a role as a pigmentary hormone in humans. There are two main reasons for this. First, despite the observations in the 1960s that alpha-MSH increased skin darkening in humans, there are reports that the peptide has no effect on melanogenesis in cultured human melanocytes. Second, the human pituitary, unlike that of most mammals, secretes very little alpha-MSH and circulatory levels of the peptide in humans are extremely low. However, there is now evidence from several groups that alpha-MSH is capable of stimulating melanogenesis in cultured human melanocytes. Rather than producing an overall increase in melanin production, it appears that the peptide acts specifically to increase the synthesis of eumelanin. Such an action could well explain the previously observed skin darkening effects of alpha-MSH. It is also now known that alpha-MSH is not produced exclusively in the pituitary but has been found at numerous sites, including the skin where it is produced by several cell types. Related Proopiomelanocortin (POMC) peptides such as ACTH are also produced in human skin. The ACTH peptides act at the same receptor (MC-1) as alpha-MSH and certain of these would appear to be more potent than alpha-MSH in stimulating melanogenesis. The ACTH peptides are also present in greater amounts than alpha-MSH in human epidermis and it is likely that they play an important role in regulating pigmentary responses. These POMC peptides are released from keratinocytes in response to ultraviolet radiation (UVR) and it has been proposed that they serve as paracrine factors in mediating UV induced pigmentation. Their production by keratinocytes could therefore be critical in determining pigmentary responses and any changes in the availability of these POMC peptides might explain the variations in tanning ability seen in different individuals. However, the possibility that tanning ability is also dependent upon differences at the level of the MC-1 receptor cannot be ruled out and it has been suggested that an inability to tan may depend upon the presence of non-functional changes at the MC-1 receptor. alpha-MSH does, of course, affect human melanocytes in several ways and its stimulation of melanogenesis could be the consequence of some other fundamental action in the melanocyte. The peptide also has many other target sites in the skin and while it may have a role in regulating skin pigmentation in humans, it should not be viewed solely as a pigmentary peptide. alpha-MSH clearly has many different actions and its primary role in the skin may be to maintain homeostasis.