Nonmelanoma skin cancers, including basal cell carcinomas and squamous cell carcinomas, represent the most common malignant neoplasms in humans. Although many environmental and genetic factors contribute to the development of skin cancers, the most important is chronic exposure to UV radiation in sunlight. We now appreciate that the role of UV in the development of nonmelanoma skin cancers is 2-fold. First, UV radiation causes mutations in cellular DNA. Failure to repair these genetic alterations ultimately leads to unrestrained growth and tumor formation. Second, UV radiation has profound effects on the cutaneous immune system, inducing a state of relative immunosuppression that prevents tumor rejection. The purpose of this review is to educate clinical dermatologists about the recent developments in molecular biology and immunology that have greatly enhanced our understanding of how skin cancers arise. The clinical implications of this new knowledge are far-reaching and likely to soon impact the diagnosis, treatment, and prevention of a variety of benign and malignant skin conditions. It will be important for the clinician to understand the biological mechanisms underlying these new therapeutic developments to implement them effectively.