Melanoma is the deadliest form of skin cancer, with no cure for advanced disease. We propose a strategy for melanoma prevention based on using analogs of -melanocyte stimulating hormone (-MSH) that function as melanocortin 1 receptor (MC1R) agonists. Treatment of human melanocytes with -MSH results in stimulation of eumelanin synthesis, reduction of apoptosis that is attributable to reduced hydrogen peroxide generation and enhanced repair of DNA photoproducts. These effects should contribute to genomic stability of human melanocytes, thus preventing their malignant transformation to melanoma. Based on these findings, we synthesized and tested the effects of 3 tetrapeptide -MSH analogs, Ac-His-D-Phe-Arg-Trp-NH₂, n-Pentadecanoyl- and 4-Phenylbutyryl-His-D-Phe-Arg-Trp-NH_2, on cultured human melanocytes. The latter two analogs were more potent than the former, or -MSH, in stimulating the activity of tyrosinase, thus melanogenesis, reducing apoptosis and release of hydrogen peroxide and enhancing repair of DNA photoproducts in melanocytes exposed to UV radiation (UVR). The above analogs are MC1R agonists, as their effects were abrogated by an analog of agouti signaling protein, the physiological MC1R antagonist, and were absent in melanocytes expressing loss-of-function MC1R. Analogs, such as 4-Phenylbutyryl-His-D-Phe-Arg-Trp-NH₂ with prolonged and reversible effects, can potentially be developed into topical agents to prevent skin photocarcinogenesis, particularly melanoma.--Abdel-Malek, Z. A., Kadekaro, A. L., Kavanagh, R. J., Todorovic, A., Koikov, L. N., McNulty, J. C., Jackson, P. J., Millhauser, G. L., Schwemberger, S., Babcock, G., Haskell-Luevano, C., Knittel, J. J. Melanoma prevention strategy based on using tetrapeptide -MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity.