Biologically and therapeutically important hypoxia occurs in many solid tumor masses. Hypoxia can be a direct cause of therapeutic resistance because some drugs and radiation require oxygen to be maximally cytotoxic. Cellular metabolism is altered under hypoxic conditions. Hypoxia can result in drug resistance indirectly if under this condition cells more effectively detoxify the drug molecules. Finally, there is evidence that hypoxia can enhance genetic instability in tumor cells thus allowing more rapid development of drug resistance cells. The current review describes the effects of hypoxia on tumor response to a variety of anti-cancer agents and also describes progress toward therapeutically useful methods of delivering oxygen to tumors in an effort to overcome therapeutic resistance due to hypoxia. Finally, the use of hypoxic cell selective cytotoxic agents as a means of addressing hypoxic 'drug resistance' is discussed.