The ability to sense and make appropriate adjustments to O2 availability is critical for normal physiological and pathological processes encountered by aerobic organisms. Therefore, the mechanisms underlying cellular responses to O2 deficiency are both biologically important and clinically relevant. Though it is recognized that probably all cells have some ability to sense O2, as will be discussed elsewhere in this volume, a major focus over the last 15 years has been on the more specialized (O2-sensing cells, including the carotid body chemoreceptors (1-3), pulmonary neuroepithelial bodies (4,5), and pulmonary vascular smooth muscle cells (6,7). In these cell types, the critical issues that are still controversial are the molecular identity and location of the O2 sensor, as well as the signaling pathways that couple the sensor to the cellular response. Whereas a neutrophil-like, membrane-associated NADPH oxidase appears to fulfill the role for the O2 sensor in pulmonary neuroepithelial bodies, based on use of an oxidase-deficient mouse model (8), the same cannot be said for the pulmonary vasculature (9) or carotid body receptors (10,11). Recent studies on pulmonary vasculature strongly favor a role for mitochondria, and heme-protein(s) in the electron transport chain, as the initial sites of oxygen sensing (6,7,12).