Reduced mitochondrial oxidative phosphorylation, via activation of adenylate kinase and the resulting exponential rise in the cellular AMP/ATP ratio, appears to be a critical factor underlying O2sensing in many chemoreceptive tissues in mammals. The elevated AMP/ATP ratio, in turn, activates key enzymes that are involved in physiologic adjustments that tend to balance ATP supply and demand. An example is the conversion of AMP to adenosine via 5′-nucleotidase and the resulting activation of adenosine A2Areceptors, which are involved in acute oxygen sensing by both carotid bodies and the brain. In fetal sheep, A2Areceptors associated with carotid bodies trigger hypoxic cardiovascular chemoreflexes, while central A2Areceptors mediate hypoxic inhibition of breathing and rapid eye movements. A2Areceptors are also involved in hypoxic regulation of fetal endocrine systems, metabolism, and vascular tone. In developing lambs, A2Areceptors play virtually no role in O2sensing by the carotid bodies, but brain A2Areceptors remain critically involved in the roll-off ventilatory response to hypoxia. In adult mammals, A2Areceptors have been implicated in O2sensing by carotid glomus cells, while central A2Areceptors likely blunt hypoxic hyperventilation. In conclusion, A2Areceptors are crucially involved in the transduction mechanisms of O2sensing in fetal carotid bodies and brains. Postnatally, central A2Areceptors remain key mediators of hypoxic respiratory depression, but they are less critical for O2sensing in carotid chemoreceptors, particularly in developing lambs.