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Primary malignant brain tumors are estimated to have caused more than 12,800 deaths in the United States in 2006, and nearly 19,000 new cases are diagnosed annually in this country. The glial-derived neoplasm, or glioma, is the most aggressive type of brain tumor and accounts for 44% of all primary brain tumors. Among gliomas, the glioblastoma is the most commonly seen glial brain tumor in the United States and the most lethal worldwide. Despite very active investigation of new therapeutic models, more aggressive surgical approaches, novel delivery modalities and protocols for radiation, types and dosage of chemotherapy, and use of new signaling modifiers, only small improvements in patient outcomes have been achieved in this disease. The purpose of this review is to summarize the important aspects of tumor hypoxia in human glial brain tumors. We will describe the techniques used to measure tumor hypoxia, highlight what is currently known of the pathophysiologic and genetic mechanisms linking hypoxia with tumor progression and illustrate the significance of the oxygen effect and its role in tumor resistance to radiation and chemotherapy. We will also review therapeutic modalities to combat hypoxic tumor cell resistance and discuss the future of diagnosing and combating brain tumor hypoxia, emphasizing noninvasive imaging and novel hypoxia-modifying agents. At the conclusion of this article, the reader should have an up-to-date understanding of a concept, tumor cell oxygenation, which has the potential to help differentiate which malignant glioma patients are most likely to have good outcomes and respond to antihypoxia therapy.