A significant number of chemicals have been shown to be carcinogenic in mouse liver while lacking carcinogenic activity in other organs or tissues of mice or rats. The review focus on the reasons for the unique susceptibility of the mouse liver to these carcinogens, and the extent the carcinogenic activity of a chemical in mouse liver can be used to predict carcinogenicity in humans. Many of these mouse liver carcinogens lack genotoxic activity and as such have been proposed to be tumor promoters. The limited amount of evidence for their tumor promoting activity is reviewed. Two mechanisms are reviewed that may explain the action of non-genotoxic carcinogens in mouse liver. These are (1) direct-action on precursor cancer cells, either to accelerate their growth or to prevent their death, and (2) the selective growth advantage, resulting from regenerative hyperplasia of precursor cancer cells in response to the necrosis of normal cells produced by hepatotoxins.