The comparative evaluation of the molecular pathways involved in HCC development in mouse and rat strains differently predisposed to HCC indicates that the genes responsible for HCC susceptibility control the amplification and/or overexpression of c-Myc, the expression of cell cycle regulatory genes, and the activity of Ras/Erk, AKT/mTOR, and of the pro-apoptotic Rassf1A/Nore1A and Dab2IP/Ask1 pathways, the methionine cycle, and DNA repair pathways in mice and rats. This evidence concerns the gene RASSF5 and hepatocellular carcinoma.