Phenobarbital was the first tumor promoter for rodent liver to be associated with the 2-stage or initiation-promotion concept of carcinogenesis. In rats and mice preinitiated with genotoxic carcinogens, phenobarbital administration increases the number of hepatocellular tumors by approximately 5-fold despite its nongenotoxicity. However, in mice phenobarbital occasionally exhibits strong inhibitory effects on hepatocarcinogenesis initiated with the potent carcinogen diethylnitrosamine. Both positive and negative effects of phenobarbital on hepatocytic proliferation and apoptosis, which are mechanistically involved in the promotion stage of hepatocarcinogenesis, have been described. These complex outcomes of phenobarbital treatment and their effects on hepatocarcinogenesis in mice raise serious issues regarding extrapolation of experimental data from laboratory animals to human risk assessment. Recent work suggests that the paradoxical actions of phenobarbital on hepatocarcinogenesis can be understood by consideration of qualitative diversity in initiated lesions and differential responses to promotion stimulus.