Hypoxia Inducible Factor (HIF) is a master regulator of the transcriptional homeostatic response to oxygen deprivation. It was originally discovered in the context of regulation of erythropoietin gene expression, but subsequently shown to have a widespread role in coordinating gene expression in response to hypoxia. Two parallel mechanisms down-regulate HIF activity when oxygen is present. Enzymatic hydroxylation of HIF alpha chains at critical prolyl residues by one of three HIF prolyl hydroxylases, leads to recognition by the von Hippel Lindau tumour suppressor protein, ubiquitylation and proteasomal destruction. Enzymatic hydroxylation of an asparaginyl residue blocks co-activator recruitment, limiting the transcriptional activity of any residual HIF chains. The discovery of these pathways regulating the activity of HIF in normal tissue and cancers will be reviewed. More recent experiments on specific functions of individual components of this pathway will be discussed.