Metazoans rapidly respond to changes in oxygen availability by regulating gene expression. The transcription factor hypoxia-inducible-factor (HIF), which controls the expression of several genes, 'senses' the oxygen concentration indirectly through the hydroxylation of two proline residues that earmarks the HIF-alpha subunits for proteasomal degradation. We review the expression, regulation and function of the HIF prolyl hydroxylases or prolyl hydroxylases domain proteins, which are genuine oxygen sensors.