In today's heightened nuclear/biological/chemical threat environment, there is an increased need to have safe and effective means to protect not only special high-risk service groups, but also the general population at large, from the health hazards of unintended ionizing radiation exposures. An unfulfilled dream has been to have a globally effective pharmacologic that could be easily taken orally without any undue side effects prior to a suspected or impending nuclear/radiological event; such an ideal radioprotective agent has yet to be identified, let alone fully developed and approved for human use. No one would argue against the fact that this is problematic and needs to be corrected, but where might the ultimate solution to this difficult problem be found? Without question, representative species of the aminothiol family [e.g., Amifostine (MedImmune, Gaithersburg, Maryland)] have proven to be potent cytoprotectants for normal tissues subjected to irradiation or to radiomimetic chemicals. Although Amifostine is currently used clinically, drug toxicity, limited times of protection, and unfavorable routes of administration, all serve to limit the drug's utility in nonclinical settings. A full range of research and development strategies is being employed currently in the hunt for new safe and effective radioprotectants. These include: (1) large scale screening of new chemical classes or natural products; (2) restructuring/reformulating older protectants with proven efficacies but unwanted toxicities; (3) using nutraceuticals that are only moderately protective but are essentially nontoxic; (4) using low dose combinations of potentially toxic but efficacious agents that protect through different routes to foster radioprotective synergy; and (5) accepting a lower level of drug efficacy in lieu of reduced toxicity, banking on the premise that the protection afforded can be leveraged by post-exposure therapies. Although it is difficult to predict which of these strategies will ultimately prove to be successful, it is certain that the probability of a useful protectant being fielded is increased significantly. This is due to the resurgence of interest in radiation protection, increased resources being expended by federal agencies, and by the Food and Drug Administration's willingness to innovate relative to new approval guidance.