Accumulated understanding of the molecular networks in the state of oncogene addiction, i.e., the "Achilles' heel of cancer," has led to the development of novel targeted therapies. Using genome-wide gene expression and network analysis, we have identified "Aurora kinase B" as a unique molecule to predict the lethal recurrence of hepatocellular carcinoma (HCC) even after curative hepatectomy. Comparative genomic hybridization (CGH)-array analysis revealed the genomic instability was closely related to Aurora kinase B expression in HCC. Then, we analyzed the in vitro and in vivo effects of a selective inhibitor of Aurora kinase B on human HCC cells. Treatment with Aurora B inhibitor in vitro resulted in polyploidy and apoptotic cell death. The growth of orthotopic liver tumors was significantly suppressed by the Aurora B inhibitor. Our preclinical studies indicate that Aurora kinase B is a promising molecular target "Achilles' heel" for the treatment of aggressive HCC.