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Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related mortality worldwide. Despite decades of efforts by many investigators, systemic chemotherapy or hormonal therapy has notoriously failed to show an improvement in survival. With a median survival of 8 months, and 1- and 3-year survival rates of 20% and 5%, respectively, the effective treatment of HCC remains far from satisfactory. Better understanding of the pathogenesis of this disease, identification of molecular targets for therapeutic intervention and availability of promising molecularly targeted therapies may change this dismal picture. In this review we will focus on what is currently known about the molecular pathogenesis of HCC, and explore the currently available and future molecular based therapies targeting these pathways. Future research in this area will maximize clinical benefit while minimizing the toxicity and cost through utilization of novel targeted agents.