Members of the Fe(II)- and 2-oxoglutarate-dependent family of dioxygenases have long been known to oxidize several amino acids in various protein targets to facilitate protein folding. However, in recent years investigators have characterized several such hydroxylation modifications that serve a regulatory, rather than structural, purpose. Furthermore, the responsible enzymes seem to function directly as sensors of the cellular environment and metabolic state. For example, a cellular response pathway to low oxygen (hypoxia) is orchestrated through the actions of prolyl and asparaginyl hydroxylases that govern both the oxygen-dependent stability and transcriptional activity of the hypoxia-inducible transcription factor. Recently, a different subfamily of Fe(II)- and 2-oxoglutarate-dependent dioxygenases has been shown to carry out histone demethylation. The discovery of protein regulation via hydroxylation raises the possibility that other Fe(II)- and 2-oxoglutarate-dependent dioxygenases might also serve in a similar capacity.