Genetically modified mice with overexpressed and/or deleted genes have been used extensively to model human cancer. However, it is uncertain as to what extent the mouse models reproduce the corresponding cancers in humans. We have compared the global gene expression patterns in human and mouse hepatocellular carcinomas (HCCs) in an attempt to identify the mouse models that most extensively reproduce the molecular pathways in the human tumors. The comparative analysis of the gene expression patterns in murine and human HCC indicates that certain genetic mouse models closely reproduce the gene expression patterns of HCC in humans, while others do not. Identification of mouse models that reproduce the molecular features of specific human cancers (or subclasses of specific human cancers) promises to accelerate both the understanding of the molecular pathogenesis of cancer and the discovery of therapeutic targets. We propose that this method, comparative functional genomics, could be effectively applied to the analysis of mouse models for other human cancers.