Preclinical studies demonstrate that amifostine has the potential to selectively protect normal tissues from the harmful effects of radiation without significantly protecting neoplastic tissue. The potential value of such an agent includes reducing treatment-related toxicity and the opportunity for radiation dose escalation in the curative treatment of cancer. An increasing number of human clinical trials have been conducted that define the toxicity profile and efficacy of radioprotection by amifostine when used during fractionated radiation therapy. These trials demonstrate that amifostine is safe and practical to administer in the outpatient setting during fractionated radiation therapy. These studies also illustrate the challenge of accurately evaluating the end point of radioprotection in the clinical setting. This article reviews the recent clinical literature on amifostine, the evidence for normal tissue protection, and the lack of tumor protection by this agent, and suggests possible avenues for future investigation and application of this agent in the field of radiation oncology.