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Molecular oxygen is an absolute requirement for most organisms including all mammals.Hypoxia-inducible factors 1 and 2 (HIF-1, HIF-2, and collectively, HIF) are heterodimeric nuclear transcription factors stimulated by hypoixa and various oncogenic signaling pathways.Though HIF-1 and HIF-2 play non-redundant roles, it has been established that they are the master regulators of angiogenesis, glucose metabolism, cell survival, microenvironment remodeling and other alterations commonly required for tumor growth.Accordingly, hypoxia-inducible factors are novel therapeutic targets for tumors.Recently, early clinical trials show that several classes of anti-cancer therapeutics, including histone deacetylase inhibitors, protein kinase inhibitors, proteasomal inhibitors, heat shock protein 90 (Hsp90) inhibitors, and inhibitors of microtubule dynamics, block angiogenesis and suppress tumor growth.We found that although these drugs were not originally developed to function as HIF inhibitors, all of them actually disrupt HIF function by either reducing functional HIF-α levels, or repressing HIF transactivation activity.I will propose a "quality control" model to explain those observations collectively, and present data to illustrate the underlying molecular, cellular and biochemical mechanisms.Potential utilization of these mechanisms for the development of new therapeutics will be discussed.