Low tissue oxygen concentration has been shown to be important in the response of human tumors to radiation therapy, chemotherapy and other treatment modalities. Hypoxia is also known to be a prognostic indicator, as hypoxic human tumors are more biologically aggressive and are more likely to recur locally and metastasize. Herein, we discuss and summarize the various methods under investigation to directly or indirectly measure tissue oxygen in vivo. Secondly, we consider the advantages and disadvantages of each of these techniques. These considerations are made in light of our specific hypotheses that hypoxia should be measured as a continuum, not a binary measurement and that moderate, not severe hypoxia is of great biological consequence.