The preclinical evaluation of amifostine confirms selective protection of normal tissues against toxicity due to radiation therapy and alkylating agent chemotherapy, while largely maintaining the antitumor effects of these therapies. The mechanism of protection mediated by amifostine at the molecular, cellular, and tissue levels is not completely understood but is, in part, through scavenging oxygen-free radicals. Significant side effects related to amifostine include nausea, vomiting, and hypotension, which can be ameliorated with appropriate premedications. Ongoing studies will continue to explore the optimal use of this cytoprotective agent.