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The use of chemical radioprotectors represents an obvious strategy to improve the therapeutic index in radiotherapy. Amofostine (WR-2721) has recently been approved for use in head and neck cancer to protect against radiation-induced xerostomia. Currently, the question has arisen whether amifostine could be used for radioprotection in broader terms. Amifostine may have the potential to enable intensified treatment by ameliorating mucosal reactions that are often a limiting factor in accelerated fractionation or concomitant chemoradiation. However, it has as yet not been clarified whether sufficient amifostine to reduce mucositis can be administered before each radiation fraction without causing unacceptable toxicity. Also, the optimal dosage and schedule of amifostine in chemoradiation combinations have not yet been established. The major concern related to radioprotectiors is the potential hazard of collateral tumor protection. A number of clinical studies have concluded that amifostine does not reduce antitumor efficacy. However, not even the largest study conducted, with over 300 patients, has sufficient statistical power to detect a clinically significant reduction in tumor control rate. To put this issue ultimately to a rest, a clinical trial with a sufficient accrual to definitely rule out a tumor protective effect of amifostine needs to be conducted. Substances reducing radiation-induced toxicity by modulating the biological response to radiation injury may represent an alternative concept in radioprotection. However, such agents are still at a developmental stage., (Copyright 2003, Elsevier Science (USA). All rights reserved.)