The microenvironment of solid human tumors is characterized by heterogeneity in oxygenation. Hypoxia arises early in the process of tumor development because rapidly proliferating tumor cells outgrow the capacity of the host vasculature. Formation of solid tumors thus requires coordination of angiogenesis with continued tumor cell proliferation. However, despite such neovascularization, hypoxia is persistent and frequently found in tumors at the time of diagnosis. Tumors with low oxygenation have a poor prognosis, and strong evidence suggests this is because of the effects of hypoxia on malignant progression, angiogenesis, metastasis, and therapy resistance. The presence of viable hypoxic cells is likely a reflection of the development of hypoxia tolerance resulting from modulation of cell death in the microenvironment. This acquired feature has been explained on the basis of clonal selection-the hypoxic microenvironment selects cells capable of surviving in the absence of normal oxygen availability. However, the persistence and frequency of hypoxia in solid tumors raises a second potential explanation. We suggest that stable microregions of hypoxia may play a positive role in tumor growth. Although hypoxia inhibits cell proliferation and in tumor cells will eventually induce cell death, hypoxia also provides angiogenic and metastatic signals. The development of hypoxia tolerance will thus allow prolonged survival in the absence of oxygen and generation of a persistent angiogenic signal. We will discuss the concept of hypoxia tolerance and review mechanisms used by cancer cells to acquire this phenotype. The concept of hypoxia tolerance has important implications for current and future therapeutic approaches. Most therapeutic efforts to combat hypoxia have focused on targeting the presence of hypoxia itself. Our hypothesis predicts that targeting the biological responses to hypoxia and the pathways leading to hypoxia tolerance may also be attractive therapeutic strategies.