Protein levels as well as transactivation activity of the alpha- subunit of the heterodimeric hypoxia-inducible transcription factor HIF are regulated by iron and 2-oxoglutarate dependent hydroxylases in an oxygen-sensitive manner. Prolyl-4- hydroxylase enzymes (PHD1-3) function as cellular oxygen sensors by hydroxylating two conserved prolyl residues in HIF- alpha, leading to HIF-alpha ubiquitinylation and proteasomal degradation under normoxic conditions. In addition, asparagine hydroxylation by factor inhibiting HIF (FIH) inhibits transactivation activity by preventing interaction with the basic transcription machinery. The enzymatic activity of PHDs and FIH is reduced under hypoxic conditions, resulting in stabilization and formation of a functional heterodimeric HIF complex that induces the expression of genes involved in the adaptation to hypoxia. Interestingly, the three PHDs possess unique regulatory and functional properties. Hypoxia and hypoxia followed by reoxygenation regulate PHD2 and PHD3 isoforms in distinct manners and adjust HIF-alpha levels in a negative feedback loop. Recently, we showed that PHD2 protein levels are regulated by a member of the immunophilin family. We also identified several proteins binding to specific PHD isoforms, which act either upstream or downstream of the PHD oxygen sensors.