Non-melanoma skin cancer (NMSC) is the most frequent malignancy in the United States, with over one million new cases reported annually. Approximately 80% of NMSC are basal cell carcinomas (BCC), while the remaining 20% of NMSC are squamous cell carcinomas (SCC). BCC and SCC commonly arise in regions of the skin subjected to chronic sun exposure implicating ultraviolet radiation (UV)-induced cellular damage as the primary causative agent. While surgical excision is an effective treatment of NMSC, strategies aimed at NMSC prevention have not been exploited clinically. The application of sunscreens has been the primary means of prevention by physically blocking the absorption of UV radiation. However, sunscreens have had limited success in decreasing NMSC incidence overall, necessitating more targeted strategies against UV damage. In this review we will discuss the relevance of recently identified UVinduced cellular changes, including induction of reactive oxygen species, immune modulation, and damage to mitochondrial DNA to serve as potential targets for the chemoprevention of NMSC. Finally, we will discuss the potential of genes required for the maintenance of epithelial stem cells in the skin as therapeutic targets for cutaneous cancer.