The rationale for hypoxic cell radiosensitizers, of which misonidazole (MISO) is the most widely used drug, is based on the premise that hypoxic cells limit the cure rate of tumors to conventional radiotherapy. There is evidence that this is the case for tumors of the head and neck and possibly also for carcinoma of the cervix and lung. Despite numerous trials, however, MISO has not shown a significant clinical benefit. However, it can be demonstrated that little or no effect would have been expected at the doses of MISO used. New and more efficient radiosensitizers are now available which are more likely to produce significant improvements in local control with radiotherapy. The sulfhydryl radioprotector WR-2721 protects normal more than malignant tissues in animals from damage by radiation and chemotherapy agents. Evidence for protection of bone marrow and kidney has now been obtained for cyclophosphamide and cisplatin, respectively, in Phase I clinical trials. Sensitizers and protectors demonstrate that chemical modification of the therapeutic index is possible for both radiation and chemotherapy treatment of cancer.