A ubiquitous pathway by which mammalian cells sense and respond to changes in oxygen availability relies upon the hypoxic induction of a transcription factor, HIF. HIF in turn activates the expression of an assemblage of genes promoting compensatory shifts in the capacity for anaerobic metabolism, O2 delivery, and other adaptive processes. The stability and activity of HIF are each regulated as a function of O2. Both mechanisms are directly mediated by posttranslational modification of this transcription factor: hydroxylation of proline and asparagine residues, respectively. These modifications are performed by members of the Fe(II)- and 2-oxoglutarate-dependent dioxygenase family whose activities are directly and indirectly dependent on cellular O2 levels. As such, these oxygenases fill a role as environmental and metabolic sensors, a paradigm that may extend to other biological pathways.