Microenvironmental elements can directly contribute to the induction and the maintenance of tumor. Oxygen is the main element in the cell microenvironment and hypoxia can affect the process of tumorigenesis. In response to hypoxia, cells change their pattern and characteristics. These changes suggest that it is not just adaptation, but some sort of cell defense against hypoxia. If hypoxia is corrected, then cell defense mechanisms are interrupted. An examination of the process of tumorigenesis helps to design better therapeutic strategies.A systematic review of the English literature was conducted by searching PubMed, Google Scholar, and ISI Web databases for studies on changes that defend and help cells to live in a hypoxic microenvironment. Cells respond to hypoxia by de-differentiation and an increase in heat shock proteins. Angiogenesis and deviation of inflammatory response in favor of hypoxic cell survival also defend and save the oxygen-starved cells from death. Finally, anti-angiogenic therapies and more hypoxia enhance metastasis, as tumors with low oxygen concentration are more malignant than tumors with high oxygen concentration. All these enable cells to migrate away from low oxygen areas and seek a more conducive microenvironment. Therapies that make the microenvironment more hypoxic need to be revised. This has been done for antiangiogenic therapies, previously considered to be anti-tumor approaches. Effective therapies may be <em>correcting therapies</em> which direct the tumor microenvironment towards natural physical/chemical condition. <em>Correcting therapies</em> either bring back tumor cells to a normal form (correct tumor cells) or help the immune system to eradicate tumor cells which can not be corrected.