Carotid body arterial chemoreceptors are essential for a normal hypoxic ventilatory response (HVR) and ventilatory acclimatization to hypoxia (VAH). However, recent results show that O(2)-sensing in the brain is involved in these responses also. O(2)-sensing in the rostral ventrolateral medulla, the posterior hypothalamus, the pre-Bötzinger complex and the nucleus tractus solitarius contribute to the acute HVR. Chronic hypoxia causes plasticity in the brain that contributes to VAH and represents another time domain of central O(2)-sensing. The cellular and molecular mechanisms of acute O(2)-sensing in the brain remain to be determined but they appear to involve O(2)-sensitive ion channels and heme oxygenase-2, which acts by a different mechanism than has been described for the carotid body. It is not known if plasticity in such mechanisms of acute central O(2)-sensitivity contributes to VAH. However, O(2)-sensitive changes in gene expression in the brain do contribute to VAH and demonstrate another mechanism of O(2)-sensing that is important for ventilatory control. This time domain of O(2)-sensing in the brain involves gene expression under the control of hypoxia inducible factor-1+/- (HIF-1+/- and potentially several HIF-1+/- targets, such as erythropoietin, endothelin-1, heme oxygenase and tyrosine hydroxylase.