Genetically modified mice have been extensively used for analyzing the cellular and genetic events that occur during the multistage progression of neoplastic development. However, in many cases, if not all, it is uncertain to what extend the mouse models faithfully reproduce features observed in the corresponding human conditions1-3. This is largely due to lack of methods for direct comparisons of mouse human tumors at the molecular level. To obtain direct comparison of the molecular features of mouse and human hepatocellular carcinoma (HCC), gene expression patterns of 68 HCC from 7 different mouse models were characterized and compared with 91 human HCC from pre-defined subclasses.Gene expression patterns of HCC from Myc, E2f1, and Myc/E2f1 mice had highest similarity with the better survival group of human HCC, while the expression patterns of Myc/Tgfa and DENA-induced mouse HCC had the highest similarity with the poorer survival group of human HCC. As expected, gene expression patterns of Acox1 knockout and ciprofibrate-induced HCC had highest similarity to each other, but failed to emulate those observed in human HCC. We conclude that our approach, the comparative functional oncogenomics, has the great potential to identify the most appropriate mouse models to study human cancers.