Tumour necrosis factor-α (TNF-α) deficient mice (TNF-α−/− mice) are resistant to skin carcinogenesis. Cellular signalling via the transcription factor complex AP-1 is thought to play a key role in tumour promotion. The induction of a specific subset of AP-1 responsive genes thought to be important for tumour development, namely GM–CSF, MMP-9 and MMP-3, was suppressed in TNF-α−/− compared to wild-type mouse skin in response to the tumour promotor TPA. The differential induction of these genes correlated with a temporal shift in AP-1 activation and c-Jun expression in TNF-α−/− compared to wild-type epidermis. The major receptor for TPA-induced signalling in basal keratinocytes, PKCα, was also differentially regulated in wild-type compared with TNF-α−/− epidermis. A marked delay in TPA-induced intracellular translocation and downregulation of PKCα was observed in TNF-α−/− epidermis, which correlated with the deregulated TPA-induced AP-1 activation and c-Jun expression. The frequency of DNA adduct formation and c-Ha-ras mutations was the same in wild-type and TNF-α−/− epidermis after DMBA treatment, suggesting that TNF-α was not involved in tumour initiation. These data suggest that the pro-inflammatory cytokine TNF-α is a critical mediator of tumour promotion, acting via a PKCα-and AP-1-dependent pathway. This may be one mechanism by which chronic inflammation increases susceptibility to cancer.