The Hypoxia-inducible factor (HIF) transcription complex, which is activated by low oxygen tension, controls a diverse range of cellular processes including angiogenesis, erythropoiesis, bronchodilatation, and cellular metabolism targeted at increasing oxygen delivery to tissues. HIF consists of the subunits HIFα and HIFβ. Whereas the HIFβ subunit is constitutive, HIFα is tightly regulated by oxygen levels through various mechanisms that include protein stability, transcription co-activator recruitment and subcellular localization. The molecular mechanism that controls HIFα protein stability has been characterized in detail. In normoxia, HIFα is ubiquitinated and degraded at the 26S proteasome, while in hypoxia the protein is stabilized. HIFα ubiquitination in normoxia is mediated by the Von Hippel Lindau (VHL) tumor suppressor factor which is the substrate recognition subunit of a multimeric E3 ubiquitin ligase complex. Physical interaction between VHL and HIFα requires hydroxylation of 2 key prolyl residues in the HIFα sequence (P402 and P564 in human HIF-1α), which is catalyzed by the specific prolyl-4-hydroxylases, named PHD1- PHD2 and PHD3 (EC 1.14.11.29). Under hypoxia, PHD hydroxylase activity is reduced; HIFα escapes hydroxylation and proteolysis, leading to HIF nuclear accumulation and transcriptional induction of target genes.