Radiation therapy is in the front line for treatment of localized prostate cancer. However, a significant percentage of patients have radiation-resistant disease. The NF-kappaB pathway is an important factor for radiation resistance, and the classical (canonical) pathway is thought to confer protection of prostate cancer cells from ionizing radiation. Recently, the alternative (non-canonical) pathway, which is involved in prostate cancer aggressiveness, has also been shown to be important for radiation resistance in prostate cancer. The alternative NF-kappaB pathway component RelB protects prostate cancer cells from the detrimental effects of ionizing radiation, in part, by stimulating expression of the mitochondria-localized antioxidant enzyme manganese superoxide dismutase (MnSOD). Blocking RelB activation suppresses MnSOD expression and sensitizes prostate cancer cells to radiation. These results suggest that RelB-mediated modulation of the antioxidant capacity of prostate cancer cells is an important mechanism of radiation resistance. Therefore, targeting RelB activation may prove to be a valuable weapon in the oncologist's arsenal to defeat aggressive and radiation-resistant prostate cancer.