Soy isoflavones have demonstrated chemopreventive and anticancer properties in epidemiology and biological studies, in addition to their function as antioxidants in prevention of cardiovascular disease. We have explored the potential of soy isoflavones, as a safe biological approach, to enhance the efficacy of radiotherapy for local tumor control and limit normal tissue damage in solid tumors. This review presents studies investigating the interaction between soy isoflavones and radiation in different malignancies, including prostate cancer, renal cell carcinoma, and nonsmall cell lung cancer. Soy isoflavones were found to be potent sensitizers of cancer cells to radiation causing increased cell killing in vitro in human tumor cell lines and greater tumor inhibition in vivo in preclinical orthotopic murine tumor models. In the course of these studies, radioprotection of normal tissues and organs in the field of radiation was observed both in a clinical trial for prostate cancer and in preclinical models. The mechanisms of radiosensitization and radioprotection mediated by soy isoflavones are discussed and emphasize the role of soy isoflavones in increasing radiation effect on tumor and mitigating inflammatory responses induced by radiation in normal tissues. Soy isoflavones could be used as a safe, nontoxic complementary strategy that simultaneously increases radiation effectiveness on the malignancy while reducing damage in normal tissues in the field of radiation.