Although the zebrafish has many attributes of a promising cancer model, one outstanding question is how similar zebrafish and human tumors are at the molecular level. To date, supporting data from histology and 'gene-to-gene' comparisons with human data offer limited insights. Using comparative microarray analyses, we found striking molecular similarities between zebrafish and human liver neoplasia. Our data indicate that zebrafish liver tumors possess the general molecular hallmarks of human liver cancer and some of the molecular similarities extend to the progression of liver tumors. The molecular conservation between fish and human liver tumors underscored the strong association and fundamental importance of these genes in liver neoplasia as well as their clinical potentials as diagnostic markers and/or therapeutic targets. In addition, our comparative oncogenomic work provides a general framework for comparing and validating microarray data of zebrafish model with human cancer, thus adding confidence of using the zebrafish to model human cancers.