It is now well established that most animal solid tumors contain oxygen-deficient hypoxic cells and that these cells will influence the response of those tumors to radiation. Identifying hypoxic cells in human tumors has proven more difficult, primarily because most of the direct procedures used in animals are not applicable to humans. However, substantial indirect evidence, which goes back to as early as 1909, clearly indicates the presence of hypoxia in human tumors, although with a considerable heterogeneity among individual tumors. Experimental studies during the last 30 years have shown that this source of radiation resistance can be effectively eliminated by a variety of procedures that include high oxygen-content gas breathing, nitrometric radiation sensitizers, blood transfusions, hemoglobin-oxygen affinity modifiers, and nicotinamide. A number of these procedures have also been tested clinically such that by 1995 over 10,000 patients in 83 randomized trials had undergone treatment designed to modify tumor hypoxia before radiation therapy. Although a number of these trials showed no benefit, an overview analysis showed that modification of tumor hypoxia significantly improved the locoregional tumor control after radiotherapy with an odds ratio of 1.21 (95% confidence interval 1.12-1.30). The treatment benefit could mostly be related to an improved response in head and neck with odds ratio 1.31 (1.19-1.43) and to a lesser extent in bladder tumors; no significant effect was observed in other tumor sites (cervix, lung and esophagus). Similar to the local control benefit, the overall survival rate improved with an overall odds ratio of 1.13 (1.05-1.21). The overall results thus showed that the biological issue related to hypoxia appears to be a sound rationale, which may impact the outcome of radiotherapy, especially with head and neck carcinoma. However, despite this wealth of positive data, "hypoxic modification" still has no impact on general clinical practice.