The etiology of liver cancer is well known, but despite recent progress in the application of molecular techniques for the analysis of the development of these tumors, we still lack precise knowledge about pathogenesis of hepatocellular carcinoma (HCC). Animal models can provide essential knowledge about HCC pathogenesis, particularly if they mimic the tissue environment in which human tumors develop. The synergism between studies in animal models and human tumors is strengthened by using comparative genomic analysis to identify genes and pathways that are critical for both mouse and human oncogenesis. In this article, the authors discuss some selective examples of constitutive, conditional, and inducible models of HCC development, and briefly describe the genetic manipulations required for engineering these models and some new techniques used for gene screening in HCC. The authors focus on models that best correlate with the human disease and offer important insights into the pathogenesis of HCC.