The cellular response to a lack of oxygen revolves around a transcription factor termed hypoxiainducible factor (HIF), which regulates processes such as energy metabolism, angiogenesis and apoptosis. When oxygen is present, prolyl and asparaginyl hydroxylases use it to hydroxylate HIFα, targeting the transcription factor for degradation and inactivation, respectively. In a Commentary on p. 3041, Norma Masson and Peter Ratcliffe discuss studies that are helping us to understand these interesting enzymes, which are members of a 2-oxoglutarate (2-OG)-dependent oxygenase superfamily. The prolyl hydroxylases(PHD1-PHD3) hydroxylate two proline residues within LxxLAP motifs in the HIFα oxygen-dependent-degradation domain (ODD). This allows the residues to bind to a pocket within the von-Hippel-Lindau (pVHL) tumour suppressor protein - the substrate-recognition component of the E3 ubiquitin ligase complex responsible for proteolysis of HIFα. The asparaginyl hydroxylases (FIHs) hydroxylate an asparagine residue within the HIFαC-terminal transactivation domain (C-TAD). This prevents it from recruiting co-activators such as p300, blocking HIF-dependent transcription. The direct incorporation of molecular oxygen at the site of hydroxylation makes these enzymes well suited to oxygen sensing. Moreover, they require multiple co-factors and co-substrates, which probably contributes to their regulatory potential.