Hepatocytes have a remarkable proliferative capacity, but are quiescent in normal liver. Cell cycle activation in hepatocarcinogenesis can be directly triggered by overexpression of single and combinations of genes or be initiated indirectly by compensatory proliferation in response to liver injury. Work with transgenic and knockout mice indicate that regardless of the initiating cause, constitutive hepatocyte proliferation accompanied by genomic damage are essential factors for liver tumor development. The carcinogenic process is best described as a continuum that involves unregulated hyperplasia, dysplasia, and adenoma formation. The critical steps required for the transition from regulated to constitutive hepatocyte proliferation and the mechanisms of genomic damage in proliferating cells are being investigated. This knowledge should be directly applicable to studies of human liver tumorigenesis.