Radiation therapy is one of the major treatment modalities in the management of human cancer. While impressive progress like more accurate dosimetry and more precise methods of radiation targeting to tumor tissue has been made, the value of radiation therapy in tumor control may have reached a plateau. At present, two opposing hypotheses regarding the use of antioxidants during radiation therapy have been proposed. One hypothesis states that supplementation with high doses of multiple micronutrients including high dose dietary antioxidants (vitamins C and E, and carotenoids) may improve the efficacy of radiation therapy by increasing tumor response and decreasing some of its toxicity on normal cells. The other hypothesis suggests that antioxidants (dietary or endogenously made) should not be used during radiation therapy, because they would protect cancer cells against radiation damage. Each of these hypotheses is based on different conceptual frameworks that are derived from results obtained from specific experimental designs, and thus, each may be correct within its parameters. The question arises whether any of these concepts and experimental designs can be used during radiation therapy to improve the management of human cancer by this modality. This review has analyzed published data that are used in support of each hypothesis, and has revealed that the current controversies can be resolved, if the results obtained from one experimental design are not extrapolated to the other. This review has also discussed the scientific rationale for a micronutrient protocol that includes high doses of dietary antioxidants (vitamin C, vitamin E succinate and natural beta-carotene) which can be used adjunctively with radiation therapy.