Cutaneous melanoma has undergone a revolution in therapeutic success during the past decade, due to major advances in both targeted therapy and immune therapies. Major insights have been gained through increased understanding of the pathways giving rise to melanoma through, for example, UV mutagenesis. Additional insights have come from an understanding of the pathway through UV induces melanin biosynthesis, which aside from triggering melanogenesis also stimulates beta-endorphin synthesis. Additional information has been gained through studies of the unique chemical consequences of red/blond pheomelanin pigments. This lecture will present studies on the role of UV induced neo-antigens in melanoma immunotherapy responses, as well as the significance of epitope spreading in the immune response, which offers novel therapeutic opportunities.