Mammalian cells respond to UV radiation by signaling cascades leading to activation of transcription factors, such as activated protein 1, NFκB, and p53, a process known as the 'UV response.' Nuclear factor of activated T cells (NFAT) was first identified as an inducible nuclear factor in immune response and subsequently found to be expressed in other tissues and cells. To date, however, the regulation and function of NFAT in tissues and cells, other than the immune system, are not well understood. In this study, we demonstrate that UV radiation activates NFAT-dependent transcription through a calcium-dependent mechanism in mouse epidermal JB6 cell lines, as well as in the skin of NFAT-luciferase reporter transgenic mice. Exposure of JB6 cells to UV radiation leads to the transactivation of NFAT in a dose- dependent manner. A23187 had a synergistic effect with UV for NFAT induction, whereas pretreatment of cells with nifedipine, a calcium channel blocker, dramatically impaired the NFAT activity induced by either UV or UV plus A23187. Calcium-dependent activation of NFAT by UV was further confirmed by an in vivo study using NFAT-luciferase reporter transgenic mice. These results demonstrated that UV radiation is a strong activator for skin NFAT transactivation through calcium-dependent pathways, suggesting that NFAT activation may be a part of the UV response.