Most histopathological classifications of human cancers include significant numbers of hypoxic cells. There is increasing evidence that, at least in certain types of human solid tumors, there is a positive relationship between the presence of hypoxia and poor outcome after radiation therapy alone or radiation combined with other therapies. Hypoxia appears to be an independent prognostic factor. There is evidence for enhanced malignant progression associated with hypoxia, including locoregional invasion and distant metastases. The presence of hypoxia may negatively affect outcome by induction of radiation resistance by the classical oxygen effect and/or by effects on gene expression and malignant progression, causing more aggressive locoregional and distant disease. It is now clear that hypoxia has the potential to influence expression of genes and activities of associated proteins that regulate growth and tissue homeostasis, resulting in cellular phenotypic heterogeneity. The molecular pathways involved in signaling and regulating changes in gene activities in response to external stresses such as hypoxia are becoming known. Identification of patients with hypoxic tumors will lead to improved selective therapy.