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, O-2 delivery, and other adaptive processes. The stability and activity of HIF are each regulated as a function of O-2. Both mechanisms are directly mediated by post translational 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 O-2 levels. As such, these oxygenases fill a role as environmental and metabolic sensors. a paradigm that may extend to other biological pathways. (c) 2005 Elsevier Inc. All rights reserved.