Our studies have focused on the role of arachidonic acid and its products in chemically and UV light-induced murine models of skin carcinogenesis, with an emphasis on determining the importance of prostaglandins (PGs), which are synthesized by the two isoforms of cyclooxygenase (COX). Different types of tumor promoters elevate COX-2 expression in keratinocytes, with little change in COX-1, suggesting that there are multiple signaling pathways by which COX-2 expression can be regulated. We found that the expression of both COX isoforms is increased by treatment with PGs and that this autoregulation occurs via PG receptors linked to a cAMP signaling pathway. We also observed that COX-2 is constitutively upregulated in papillomas and carcinomas from either chemical initiation-promotion or UV-irradiation carcinogenesis experiments. We next investigated cis- and transacting factors required for COX-2 expression. Two regions of the COX-2 promoter, an E box and a nuclear factor-IL6 (NF-IL6) site, were identified as positive regulatory elements through transient transfection with luciferase reporter vectors containing various 5'-flanking regions of the promoter. We found that overexpression of COX-2 in tumors maybe caused by a dysregulation in the expression pattern of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors. To demonstrate the importance of PG synthesis in the carcinogenesis process, several nonsteroidal anti-inflammatory (NSAIDs) drugs were administered either orally or topically during UV carcinogenesis. Dietary administration of indomethacin, piroxicam, or the selective COX-2 inhibitor celecoxib prevented the development of UV-induced skin cancers by up to 85%. In addition, celecoxib had therapeutic efficacy in that it caused regression of preexisting tumors. Topical administration of indomethacin after each UV exposure was also effective, suggesting that a postexposure approach to skin cancer prevention maybe effective. Collectively, these studies suggest that prostaglandins play a critical role in skin cancer development.