UV radiation is an important environmental factor in the pathogenesis of skin aging and cancer. Many harmful effects of UV radiation are associated with generation of reactive oxygen species. Cellular antioxidants prevent the occurrence and reduce the severity of UV-induced photoaging and diseases of the skin. The transcription factor Nrf2 (NF-E2-related factor 2) and its negative regulator protein, Keap1 (Kelch-like-ECH-associated protein 1), are central regulators of cellular antioxidant responses. We used nrf2-null mice to investigate the roles of the Nrf2-Keap1 system in protection of skin from harmful effects of UVB irradiation. A single irradiation with UVB induced stronger and longer lasting sunburn reaction in nrf2-null mice. Histological changes, including epidermal necrosis, dermal edema, inflammatory cell infiltration, sunburn cell formation, TUNEL-positive apoptotic cell formation, and accumulation of oxidative DNA products such as 8-hydroxy-2′- deoxyguanosine after UVB irradiation, were more prominent in nrf2-null mice. These findings indicate that the Nrf2-Keap1 pathway plays an important role in protection of the skin against acute UVB reactions, including cutaneous cell apoptosis and oxidative damage. However, there were no significant differences in skin carcinogenesis between nrf2-null and wild-type mice exposed to chronic UVB irradiation, suggesting that there is a complex and subtle balance between factors promoting and preventing photocarcinogenesis.