Hepatocellular carcinoma (HCC) is a major health concern worldwide. Several therapeutic options are available, but transplantation is the only curative option; for the vast majority of patients, the remaining alternative is palliative care. There is some hope however with Lipiodol which, when injected into the hepatic artery remains concentrated in the liver and specifically within the malignant tumor for a long period of time. This feature has been used for internal radiation therapy using (131)Iodine-labeled Lipiodol. Phase III studies with (131)I-Lipiodol have demonstrated, in an adjuvant setting improved recurrence-free and overall survival compared with surgery alone and in a palliative setting improved survival among patients with portal thrombosis. Comparison with chemoembolization has shown similar results in terms of efficacy but with better tolerance for (131)I-lipiodol. The method would also be useful for small nodules not amendable to surgery or percutaneous treatment. The use of another radionuclide, (188)Re, could probably improve the current method by reducing the need for radioprotection. New perspectives will be forthcoming with the advent of targeted drugs using combinations in sequential or concomitant regimens.