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Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with increasing incidence in Western countries. Many pharmacologic treatments have been tested against HCC; most of them belong to three categories: chemotherapy, hormone therapy, and immunotherapy. Neither single agent nor combination chemotherapy have demonstrated a clear reproducible advantage in terms of overall survival; therefore, systemic or intraarterial chemotherapy should not be considered as standard strategies for patients with HCC. Tamoxifen and antiandrogen therapy were not effective in prolonging survival when tested in randomized, controlled trials. Promising results have been obtained with octreotide in a small randomized trial, but confirmation studies are needed. Although adoptive immunotherapy was effective in the adjuvant setting, interferon should be further investigated in this setting or investigated as a preventive strategy in cirrhotic patients. On the contrary, interferon does not seem to have a role in advanced disease, where it is tolerated poorly. In the future, innovative and promising therapeutic strategies will be tested in HCC, including new biologic target-based drugs, cyclooxygenase inhibitors, and gene therapy.