The molecular pathogenesis of HCC is very complex and involves different pathways and molecular aberrations such as RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, VEGF, c-Met, and HDACs, simultaneous or sequential elimination of the function of these key pathways or key molecules may improve the therapeutic dilemma of HCC patients. This evidence concerns the gene EPHB2 and hepatocellular carcinoma.