Hepatocellular carcinoma (HCC) is currently the fifth most common solid tumor worldwide and the third leading cause of cancer-related death. Eighty percent of new cases occur in developing countries, but the incidence is rising in economically developed regions including Japan, Western Europe, and the United States. More than 80% of patients present with advanced or unresectable disease, and for those patients who do undergo resection, the recurrence rates can be as high as 50% at 2 years. Thus, a large number of patients will seek systemic therapy. Systemic cytotoxic chemotherapy is largely ineffective and can have significant toxicity in patients with underlying liver dysfunction. Newer biologic agents that target molecular abnormalities common to HCC may improve the clinical outcome in patients with HCC.