The effects of UVR on the skin include tanning, carcinogenesis, immunomodulation, and synthesis of vitamin D, among others. Melanocortin 1 receptor polymorphisms correlate with skin pigmentation, UV sensitivity, and skin cancer risk. This article reviews pathways through which UVR induces cutaneous stress and the pigmentation response. Modulators of the UV-tanning pathway include sunscreen agents, melanocortin 1 receptor activators, adenylate cyclase activators, phosphodiesterase 4D3 inhibitors, T-oligos, and microphthalmia-associated transcription factor regulators such as histone deacetylase inhibitors. UVR, as one of the most ubiquitous carcinogens, represents both a challenge and an enormous opportunity in skin cancer prevention.