HIF-1 is a transcription factor which acts as a master regulator co-ordinating oxygen homeostasis. An oxygen sensitive signal controlling HIF-1 is provided by enzymatic hydroxylation reactions which require molecular oxygen and modify specific prolyl and asparaginyl residues in the HIF a subunit. These act as switches – enabling capture by a specific ubiquitin ligase, and preventing transactivator recruitment. An important challenge is to understand how this simple principle is used to tailor the oxygen response system to the diverse settings that occur in complex organisms such as ourselves. The emerging picture is of many parameters which are likely to contribute, including cofactor availability and regulated expression of the hydroxylase enzymes.