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The use of external beam radiation therapy for primary treatment of hepatocellular carcinoma (HCC) has been limited by the low radiation tolerance of the non-tumoral liver. However, technical advances allowing partial liver volume external irradiation have resulted in consistently high response rates. Internal radiation therapy, also called (90)Y radioembolization ((90)Y-RE), consists in delivering implantable microspheres labeled with (90)Y into the arteries that feed liver tumors in order to provide a high dose of radiation to tumor nodules irrespective of their number, size and location, while preserving the non-tumoral liver tissue from receiving a harmful level of radiation. Among patients with HCC, (90)Y-RE is used for those that have a preserved liver function and unresectable tumors that cannot be treated with percutaneous ablation. Although (90)Y-RE is by and large well tolerated, it may produce relevant toxic effects as a result of radiation of non-target organs including cholecystitis, gastrointestinal ulceration, pneumonitis, and most importantly, liver toxicity. A significant effect on tumor growth in the treated lesions is consistently observed with disease control rates in excess of 80%. Also, (90)Y-RE may allow downstaging large or multiple lesions to radical treatments with curative intent. When compared with the survival of HCC patients in advanced stage either not treated or treated with ineffective systemic agents, survival after (90)Y-RE is encouraging and warrants future clinical trials. Clinical research in combining the cytotoxic effect of (90)Y with the cytostatic mechanism of targeted therapies is currently in progress and will provide valuable safety and toxicity data that may translate into improved clinical outcome and overall survival.