Hepatocellular carcinoma (HCC) is not only common, but often presents at a stage when potentially curative therapies are not feasible. Although hepatic artery chemoembolization likely confers survival benefit in unresectable HCC, the associated toxicities are substantial and warrant investigation of more efficacious and safe therapies. Many patients who present with unresectable HCC are not chemoembolization candidates, either because of extensive disease or severely impaired hepatic function. We reviewed 44 randomized trials investigating non-embolization-based therapies in unresectable HCC. Hepatic artery infusion of [I]lipiodol appears safe; initial studies suggest a survival benefit and efficacy comparable to more toxic embolization-based therapies. Some cytotoxic chemotherapy may confer a modest survival benefit in advanced HCC (including oral fluoropyrimidines, and hepatic arterial or i.v. cisplatin and doxorubicin). Tamoxifen does not confer survival benefit, either in advanced or limited HCC. Other therapies warranting further study include interferon (in optimally cytoreduced HCC), megestrol in patients with variant estrogen receptors, octreotide and pravastatin. More adequately powered, rigorously conducted studies will hopefully identify useful chemo-, radio-, immuno-, embolization-based and biologically targeted therapies during the next decade.