Sensing and responding to changes in oxygen partial pressure assures that the cellular oxygen supply is tightly controlled in order to balance the risks of oxidative damage vs. oxygen deficiency. The hypoxia inducible factor (HIF) regulatory system is controlled by prolyl hydroxylases (PHDs), the von Hippel Lindau protein (pVHL), and the 26S proteasome and transduces changes in oxygenation to adequate intracellular adaptive responses. A functional HIF response requires stabilization of the α-subunit, e.g. HIF-1α, during hypoxia and dimerization with HIF-1β, to drive target gene activation. Intriguingly, high concentrations of nitric oxide (NO) stabilize HIF-1α and thus mimic a hypoxic response under normoxia. Mechanistically, NO blocks PHD activity and attenuates proline hydroxylation of HIF-1α. This causes dissociation of pVHL from HIF-1α and, consequently, HIF-1α accumulates because proteasomal destruction is impaired. However, during hypoxia low concentrations of NO facilitate destruction of HIF-1α and thus reverse HIF signaling. Under these conditions, NO impairs respiration and avoids oxygen gradients that limit PHD activity. An additional layer of complexity comprises the interaction of NO with O₂⁻. Signaling qualities attributed to NO are antagonized by compensatory flux rates of O₂⁻ and vice versa to adjust levels of HIF-1α under normoxia and hypoxia. The liaison of NO and hypoxia is versatile and ranges from courting to matrimony and divorce.