We had reported that the paracrine/autocrine factor α-melanocortin (α-MSH) reduces UV-induced DNA damage in melanocytes by enhancing the repair of DNA photoproducts, reducing the generation of reactive oxygen species, activating antioxidant enzymes and basic excision repair. These effects are critical for melanoma prevention, and are evident prior to increased pigmentation. The effects of α-MSH are mediated by activating the melanocortin 1 receptor (MC1R) and explain why loss-of-function allelic variants of the MC1R gene increase melanoma susceptibility. We observed that the keratinocyte-derived endothelin-1, a potent mitogen and melanogenic factor for melanocytes, inhibits the generation of ROS immediately after UV irradiation. Recently, we found that 1,25(OH)2vitamin D3 (vit D3), also synthesized by keratinocytes upon UVB exposure, enhances the repair of DNA photoproducts, reduces ROS generation, and increases the protein levels of enzymes involved in base excision repair in primary cultures of human melanocytes. Vitamin D3 reduced the burden of UV-induced DNA photoproducts in human skin explants, evident as profound reduction in DNA photoproducts in the entire epidermis, and in melanocytes. Melanocytes express the endothelin B receptor and vitamin D receptor. Both endothelin 1 and vitamin D3 up regulate the expression of the MC1R gene, which is predicted to increase the expression of the MC1R on melanocytes and the response to α-MSH. These results suggest that the paracrine network in the skin inhibit melanoma formation by reducing UV-induced DNA damage by a mechanism that involves up regulation of MC1R expression.