Our investigations continue to provide support for the proposal that, consequent to inhibition of mitochondrial oxidative phosphorylation, AMP-activated protein kinase (AMPK) mediates hypoxia-response coupling in all oxygen-sensing cells (Evans, 2006). Consistent with this view, we have demonstrated that physiological levels of hypoxia precipitate an increase in the ADP:ATP and AMP:ATP ratio in pulmonary arterial smooth muscle, and that this is accompanied by activation of AMPK and phosphorylation of acetyl CoA carboxylase; a well-established marker for AMPK action. Most significantly, we then showed that pharmacological activation of AMPK elicits constriction of pulmonary arteries, and in a manner that mimics precisely the mechanisms of that underpin hypoxic pulmonary vasoconstriction (Evans et al., 2005). These studies therefore suggested that activation of AMPK by hypoxia may aid ventilation-perfusion matching in the lung. The proposal that AMPK may be of general importance to hypoxia-response coupling in all oxygen-sensing cells then gained further support from our studies on the carotid body. Consistent with the effects of hypoxia, intracellular dialysis from a patch pipette of an active (thiophosphorylated) recombinant AMPK heterotrimer (α2β2γ1) or application of the AMPK activators AICAR and A769662: (1) Inhibited BKCa currents and TASK potassium currents in rat carotid body type I cells (Wyatt et al., 2007; Ross et al., 2011); (2) Inhibited whole-cell currents carried by KCa1.1 (Wyatt et al., 2007; Ross et al., 2011) and TASK3, but not TASK1 channels expressed in HEK293 cells (unpublished); (3) Triggered carotid body activation (Evans et al., 2005; Wyatt et al., 2007). We therefore sought to determine whether or not Lkb1, the upstream kinase required for activation of the AMP-activated protein kinase by energetic stress, is necessary for oxygen-sensing by the carotid body. Conditional deletion of the Lkb1 gene in mouse type I cells abolished the increase in intracellular calcium by hypoxia. Lkb1 deletion also ablated the hypoxia-evoked increase in afferent discharge in the carotid sinus nerve, and prevented the increase in breathing frequency by hypoxia in these mice (unpublished). Thus, the Lkb1-AMPK signalling pathway mediates carotid body activation by, and the ventilatory response to, hypoxia. The Lkb1-AMPK signalling pathway is therefore required for hypoxia-response coupling, and serves to regulate oxygen and thereby energy supply at the whole body level.