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Communicated by Richard WoosterThe incidence of melanoma, the most lethal form of skin cancer, continues to increase in the Western world. In addition to genetic alterations in high- and low-susceptibility genes identified for melanoma, somatic mutations inBRAFgene occur frequently in human melanoma and are distinctively linked to sun exposure. Of significance is a single hotspot codon, i.e.,BRAFV600, wherein up to 92% of all mutations arise. Recent work in our laboratory has demonstrated that solar ultraviolet (UV) irradiation triggers mutagenesis through induction of various DNA lesions, many of which capable of producing similar types of mutations, as those seen inBRAFV600 variants in human melanoma. In this review article, we have discussed application of “DNA damage-targeted mutagenicity” of solar UV-irradiation for determining the mechanistic involvement of sunlight UV inBRAFV600 mutagenesis in human melanoma. We envision that establishing “DNA-damage derived mutagenesis” in this exceptionally unique target gene may resolve the underlying mechanism(s) of melanomagenesis, thus helping define preventive and therapeutic measures against this malignant disease.