Hepatocellular carcinoma(HCC), one of the most common cancers in the world, is characterized by poor prognosis and recurrence after resection. Its prevalence is highest in developing countries, particularly where there is high incidence of hepatitis B virus infection. Several curative treatments are available for early stage HCC; however, these options are not available for advanced disease. New techniques allowing the specific delivery of high-dose radiotherapy enable their use in the treatment of HCC, which has been avoided in the past due to low hepatic tolerance for radiation. This presents a new challenge—the development of resistance to radiotherapy and subsequent disease recurrence. Recently, the mechanisms controlling radioresistance have begun to be elucidated. Understanding the molecular basis of radioresistance is key to developing new strategies with better treatment response and increased patient survival. Hepatocellular carcinoma (HCC), one of the most common cancers in the world, is characterized by poor prognosis and recurrence after resection. Its prevalence is highest in developing countries, particularly where there is high incidence of hepatitis B virus infection. available for early stage HCC; however, these options are not available for advanced disease. New techniques allowing the specific delivery of high-dose radiotherapy enable their use in the treatment of HCC, which has been avoided in the past due to low hepatic tolerance for radiation. This presents a new challenge-the development of resistance to radiotherapy and subsequent disease recurrence. Recently, the mechanisms controlling radioresistance have begun to be elucidated. Understanding the molecular basis of radioresistance is key to developing new strategies with better treatment response and increased patient survival.