Strains of laboratory mice vary markedly in their susceptibility to two-stage skin carcinogenesis using 7,12-dimethylbenz[a]anthracene (DMBA) as the initiating carcinogen and croton oil as promoter. This study has been undertaken in order to clarify the basis of the strain differences. LACA mice were used as the susceptible strain and BALB/c mice as the resistant strain. DMBA was a more effective complete carcinogen in LACA mice than in BALB/c mice. However, dose-response studies with respect to DMBA in the two strains in two-stage carcinogenesis suggested that metabolic activation of DMBA to the active carcinogen was not limiting in the resistant strain. The observed strain differences in response to DMBA in one and two stage carcinogenesis may reflect the ability of DMBA to also act as a promoter in the two strains. The possibility that the strains vary in their ability to repair damaged DNA has, however, not been eliminated. Unlike polycyclic aromatic hydrocarbon carcinogens such as DMBA, phorbol ester promoters (the active components in croton oil) do not appear to require metabolic activation. However, they are degraded and inactivated by epidermal and other cells. Experiments in which the dose and frequency of application of croton oil were increased, and the unrelated promoter anthralin was substituted for croton oil, failed to produce any evidence that differences in promoter degradation contributed to the differences in susceptibility between strains.