Vital homeostatic mechanisms monitor O₂ supply and adjust respiratory and circulatory function to meet demand. The pulmonary arteries and carotid bodies are key systems in this respect. Hypoxic pulmonary vasoconstriction aids ventilation-perfusion matching in the lung by diverting blood flow from areas with an O₂ deficit to those rich in O₂, while a fall in arterial pO₂ increases sensory afferent discharge from the carotid body to elicit corrective changes in breathing patterns. We discuss here the new concept that hypoxia, by inhibiting oxidative phosphorylation, activates AMP-activated protein kinase (AMPK) leading to consequent phosphorylation of target proteins, such as ion channels, that initiate pulmonary artery constriction and carotid body activation. Consistent with this view, AMPK knockout mice fail to adjust their ventilation rate in response to hypoxia. Thus, AMPK may be sufficient and necessary for hypoxia-response coupling and may regulate O₂ and thereby energy (ATP) supply at the whole body as well as the cellular level.