The bovine keratin 6 gene promoter was used to target expression of spermidine/spermine N1-acetyltransferase (SSAT) to epidermal keratinocytes in the hair follicle of transgenic mice. K6-SSAT transgenic mice appeared to be phenotypically normal and were indistinguishable from normal littermates until subjected to a two-stage tumorigenesis protocol. For such tumorigenesis studies, mice were bred for six generations onto a tumor promoter resistant C57BL/6 background strain. K6-SSAT transgenic mice showed a 10-fold increase in the number of epidermal tumors that developed in response to a single application of 400 nmol of the tumor initiator 7,12-dimethylbenz[a]anthracene followed by twice weekly applications of 17 nmol of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 19 weeks. Tumor samples from transgenic animals showed marked elevations in SSAT enzyme activity and SSAT protein levels compared with tumors from non-transgenic littermates, and the accompanying changes in putrescine and N1-acetylspermidine pools indicated activation of SSAT-mediated polyamine catabolism in transgenic animals. An unusually high number of tumors were shown both grossly and histologically to have progressed to carcinomas in this model and these occurred with an early latency and only in mice carrying the K6-SSAT transgene. These results suggest that activation of polyamine catabolism leading to increases in putrescine and N1-acetylspermidine may play a key role in chemically induced mouse skin neoplasia.