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With process improvements in treatment including image guidance and intensity modulation, radiation therapy remains an important component of care for patients affected with prostate carcinoma. Although radiation therapy coupled with hormone therapy can provide exceptional cure rates in patients with low and intermediate risk factors, more progress is needed for patients with high risk of failure. These patients often can present with large volume disease in the prostate with unfavorable Gleason grade and risk for disease at and beyond the prostate capsule. These patients are predominantly treated with radiation therapy for local treatment. Developing strategies to augment control with radiation therapy in parallel to hormone therapy is important for the next generation of prostate cancer patients. This paper reviews potential molecular pathways that can sensitize prostate cancer cells to radiation therapy and potentially improve the therapeutic index for patients with this disease.