Deficiencies in the oxygenation of solid tumors are associated with poor patient prognosis due to changes in cell metabolism, angiogenesis, invasiveness and resistance to therapy. Work over the past 10 years has defined several distinct oxygen sensing pathways that together determine the cellular response to hypoxia. These include both a transcriptional response initiated by oxygen-dependent stabilisation of the HIF-1 transcription factor and an mRNA translational response characterized by activation of the unfolded protein response (UPR) and inhibition of mTOR signalling. Laboratory experiments have established the importance of these hypoxic response pathways for tumor growth and resistance to treatment. This has led to the development of agents aimed at targeting hypoxic response pathways in tumors, several of which are in clinical trials. However, several important features of the tumor microenvironment that may affect the success of these new therapies have not been thoroughly evaluated. Oxygenation patterns in human tumors have proven to be highly complex, leading to a large degree of heterogeneity with respect to the severity and duration of hypoxic exposure. Because both of these properties strongly influence the known cellular responses to hypoxia, this heterogeneity is expected to be a strong determinant of the fate of hypoxic cells and the success of new hypoxia-directed therapies. Here we summarize the important oxygen response pathways that currently serve as targets for therapy and their dependence on the specific oxygenation patterns that are expected in human tumors.