Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural product shown to inhibit carcinogen-induced pre-neoplastic lesions in mouse mammary organ culture and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted mouse skin tumors. Application of TPA to mouse skin induces oxidative stress, as evidenced by numerous biochemical responses, including significant generation of H2O2 and enhanced levels of myeloperoxidase and oxidized glutathione reductase activities and decreases in glutathione levels and superoxide dismutase activity. TPA treatment also elevates the expression of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), c-myc, c-fos, c-jun, transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor-alpha (TNF-alpha). As currently reported, pre-treatment of mouse skin with resveratrol negated several of these TPA-induced effects in a dose-dependent manner. H2O2 and glutathione levels were restored to control levels, as were myeloperoxidase, oxidized glutathione reductase and superoxide dismutase activities. As judged by reverse transcriptase-polymerase chain reaction (RT-PCR), TPA-induced increases in the expression of c-fos and TGF-beta1 were selectively inhibited. These data suggest that resveratrol inhibits tumorigenesis in mouse skin through interference with pathways of reactive oxidants and possibly by modulating the expression of c-fos and TGF-beta1.