Ultraviolet A (UVA) radiation is immunosuppressive and mutagenic in humans and carcinogenic in animals. UVA suppresses immunity with a bell-shaped dose response. At doses equivalent to 15-20 minutes of sun exposure at noon, UVA contributes to approximately 75% of sunlight-induced immunosuppression. A recent action spectrum, indicating that 360-380 nm but not 320-350 nm UVA suppresses immunity in humans, suggests an important role for reactive oxygen species. UVA also causes an energy crisis in cells, and normalization of adenosine triphosphate with nicotinamide prevents UVA immunosuppression. UVA activation of the alternative complement pathway and defects in memory T-cell development are also involved. Human skin cancers contain mutations in the p53 and BRM genes that are consistent with being induced by UVA. UVA is also mutagenic in human skin equivalents. The basal layer of human skin is more susceptible to UVA-induced mutations than the upper layers. Because skin cancers arise from these basal proliferating cells, this finding is likely to be important and could be attributable to low levels of the DNA repair enzyme OGG1 in basal cells. UVA is therefore likely to make a larger contribution to UVA-induced skin carcinogenesis in humans than is predicted by small animal models as the result of being immunosuppressive and mutagenic for basal keratinocytes. Semin Cutan Med Surg 30:214-221 © 2011 Elsevier Inc. All rights reserved.