Although whole liver tolerance to radiation therapy (RT) is low, hepatocellular carcinoma (HCC) can be treated with focal high-dose RT, using a variety of advanced and specialized treatment strategies. Technical advancements in external beam RT that facilitate the safe delivery of RT to a wide spectrum of patients include conformal RT planning, breathing motion management, and image-guided RT. A variety of doses and RT fractionation schemes have been used safely alone or in combination with other therapies such as transarterial chemoembolization. Charged particles, produced from very specialized treatment units, are associated with particularly desirable dose distributions allowing tumoricidal doses to be delivered with sustained tumor control and little toxicity, even in the presence of Child-Pugh class B or C cirrhosis. Another strategy to deliver RT to HCC is hepatic arterial delivery of radioisotopes, such as microspheres tagged with yttrium-90. Liver toxicity is more likely in patients with reduced liver reserve and/or tumors infiltrating the majority of the liver. Phase II studies and a small phase III trial have demonstrated activity of hepatic arterial radioisotopes in HCC, providing rationale for large confirmatory randomized trials. Recurrences after RT occur most often within the liver, outside the high-dose irradiated volume, and outcomes after RT to very large and/or diffuse HCC are poor, providing rationale for combining RT with other therapies or novel radiation sensitizers. Given the vascular properties of HCC, there is rationale for investigating RT with anti-vascular endothelial growth factor–targeted agents.