Cancer patients report widespread use of antioxidant supplements during chemotherapy, despite recommendations by the American Institute for Cancer Research and others that supplements should not be used during treatment. These guidelines are based upon the fact that numerous chemotherapeutic agents, as well as radiation therapy, exert their cytotoxic effects by generation of reactive oxygen species (ROS), which cause massive damage to DNA and proteins and trigger apoptosis, resulting in tumor and normal cell death. Thus, there is the concern that antioxidants may block the ROS-generated effects of therapy on tumor cells. There are no data based on sound epidemiological or clinical studies to support this hypothesis, however. In fact, some experimental studies have shown that antioxidants may potentiate the effects of chemotherapeutic drugs, while also lessening treatment-related toxicities. In this report, we review the literature regarding chemotherapy and radiation therapy as sources of oxidative stress, and present the current data regarding effects of antioxidant supplement use on normal and cancer cells. The role of antioxidant supplements, as well as the role of genetic variants in oxidative stress genes, in relation to cancer treatment toxicities and survival are discussed.