The incidence of skin cancer is rising, and significantly linked to carcinogenic effects of ultraviolet radiation. While clashes in lifestyle and cancer risk have undoubtedly contributed to this health crisis, it is equally clear that certain human populations have a notably lower risk of skin cancer. This apparent natural protection, typically afforded by darker skin pigmentation or an easy ability to tan, has begun to reveal mechanistic insights of great relevance to skin cancer risk. An understanding of the genes that participate in pigmentation and the sun-tanning response has permitted greater understanding of the intracellular and intercellular signaling events that culminate in human skin pigmentation. Moreover the same observations have also suggested novel targeted approaches to mimic the pigmentary response using agents that spare the cell from carcinogenic effects of ultraviolet radiation. The application of such strategies is not yet at hand, but potentially promises to provide a complementary approach to prevention of cutaneous cancer.