Immunoreactive alpha-MSH was found in human skin and the skin of numerous other mammals. After hypophysectomy the concentration of alpha-MSH in rat skin showed little change suggesting that the pituitary is not the source of this MSH. In human skin the highest concentration was found in the epidermis and HPLC revealed four peaks of immunoreactive alpha-MSH. Two of these co-eluted with mono- and des-acetyl alpha-MSH standards. An earlier peak probably represented an oxidized MSH and a later running peak, diacetylated alpha-MSH. Although no differences were found in alpha-MSH content of skin from albino and pigmented rats or between involved and non-involved epidermis of patients with vitiligo, its predominance in human epidermis could suggest a relationship with the melanocyte or its melanin. Whether alpha-MSH in the skin has any pigmentary significance or any other role has yet to be established.