Cytochrome c oxidase (CcO; complex IV of the mitochondrial electron transport chain) is the primary site of cellular oxygen consumption and, as such, is central to oxidative phosphorylation and the generation of adenosine-triphosphate. Nitric oxide (NO), an endogenously-generated gas, modulates the activity of CcO. Depending on the intracellular oxygen concentration and the resultant dominant redox state of CcO, the interaction between CcO and NO can have a range of signaling consequences for cells in the perception of changes in oxygen concentration and the initiation of adaptive responses. At higher oxygen concentrations, when CcO is predominantly in an oxidized state, it consumes NO. At lower oxygen concentrations, when CcO is predominantly reduced, NO is not consumed and accumulates in the microenvironment, with implications for both the respiratory rate of cells and the local vascular tone. Changes in the availability of intracellular oxygen and in the generation of reactive oxygen species that accompany these interactions result in cell signaling and in regulation of oxygen-sensitive pathways that ultimately determine the nature of the cellular response to hypoxia.