Hypoxia is a characteristic of all solid tumors analyzed to date and is rarely detected in physiologically normal tissues. The severity of tumor hypoxia has been linked with advancing tumor grade and is a prognostic indicator for poor radiotherapy outcome. Hypoxia has also been linked with resistance to chemotherapy that can be achieved through multiple mechanisms. A number of approaches can be taken to therapeutically target this population. The activity of the HIF-1 transcription factor that governs the adaptive response to oxygen deprivation can be inhibited using small molecule or gene therapy based strategies. Alternatively, HIF-1 can be hijacked to switch on therapeutic gene expression specifically in hypoxic tumor cells. To add further stringency to the latter approach bioreductive pro-drugs can be used that may reduce the potential for systemic cytotoxicity. Data accrued both in vitro and in vivo suggest that both of these approaches will yield significant enhancement in the efficacy of conventional therapy and will warrant clinical evaluation in the near future.