Hypoxic modification has been the subject of investigations in clinical radiation oncology since the early 60s. To date, this has not yet resulted in a treatment that has been widely accepted. Logistics and technical difficulties limit the routine use of hyperbaric oxygen in radiotherapy. The nitroimidazoles have not gained general acceptance, initially because of their toxicity and later because of doubts about the effectiveness of the newer generation of less toxic drugs. Nevertheless, there is good evidence from these studies that improving clinical outcome by hypoxic modulation is an achievable goal. Newer approaches including combinations of radiotherapy with tirapazamine, erythropoietin, and carbogen and nicotinamide (ARCON) are currently in phase III trial. For these new strategies to be successful, it is important that the proper patient categories are selected. Various methods to assess tumor oxygenation are now becoming available in the clinic. These potential predictive assays must be incorporated and validated in current and future large-scale clinical trials. Modifiers that target other aspects of tumor biology may also have indirect effects on tumor oxygenation. These aspects require further study in preclinical and early clinical settings.