Studies on mechanisms of radioprotection are leading to a more rational use of protectors for different applications. In considering the feasibility of radioprotectors that act through various mechanisms, it is necessary to distinguish the application needed, e.g., protection against accidental external or internal exposures, acute high-dose radiation injury or low doses over a long period, high-LET radiation exposures during space flight, and protection of normal tissues of cancer patients who are undergoing therapy. Protectors generally are classified as either sulfhydryl compounds, other antioxidants, or receptor-mediated agents (e.g., bioactive lipids, cytokines, and growth factors). This review focuses on comparative radioprotection and toxicity studies in mice using the most effective phosphorothioate agents designated as WR-compounds and other classes of protectors. The superiority of phosphorothioates (WR-2721, WR-151327) as radioprotectors appears to be related to their high affinity for DNA and the similarity in structure of phosphorothioate metabolites to polyamines, and their effects on processes related to DNA structure and synthesis. Drug tolerance levels are available from clinical trials using WR-2721 (amifostine) and provide a basis for discussions of the disadvantages of phosphorothioate administration outside a clinical setting. In this regard, arguments are presented against the current use of WR-2721 by Department of Energy personnel for planned radiation exposures during emergencies. Future research may demonstrate, however, that pharmacologic agents could be useful in accident scenarios, especially when used in combination with therapeutic measures. Assessment of potential prophylactic measures should consider compatibility with therapeutic measures currently in use or ones that might be available in the future for the treatment of radiation injuries. These include antiemetics, purified stem cells, granulocyte colony-stimulating factor, and other cytokines. Their potential usefulness against radiation-induced mutagenesis of pre- and postexposure administration of phosphorothioates and other classes of protectors should be corroborated in humans.