The study of the molecular mechanisms involved in low-oxygen chemotransduction has provided a large number of oxygen-sensitive ion channels, both in chemoreceptor and non-chemoreceptor cells. The focus in the last years has been placed in the molecular characterization of these channels, the identity of the oxygen sensor, and its link with the functional response of the cell. This search has been most extensively prosecuted in chemosensory systems involved in acute oxygen sensing such as pulmonary artery smooth muscle cells (PASMCs) carotid bodies (CBs), and airway neuroepithelial bodies (NEBs). The large amount of data regarding the molecular nature of the oxygen-sensitive ion channels and the oxygen-sensors in these preparations has modified substantially the initial hypothesis of a conserved O2-sensing mechanism. Experimental findings in these chemosensory systems cannot be reconciled into a unifying theory of a single oxygen-sensitive ion channel and a universal O2 sensor, and this fact has stimulated the building of an emerging paradigm of acute oxygen sensing that opens new and interesting theories from a physiological and pathophysiological standpoint. This new model tries to explain several well established facts, such as the heterogeneity of oxygen-sensitive ion channels within the same preparation (as there are species-related differences, and even more than one type of oxygen-modulated channel), the presence of these same channels of channel subunit combinations in oxygen-insensitive preparations and the diversity of O2-sensing mechanisms described. Altogether, these facts heighten the concept that several different mechanism have developed to ensure adequate hypoxic responses. Moreover, this concept could not only imply that chemoreceptor cells posses some “backup” or second choice mechanism to respond to hypoxia, but may also reflect the fact that the integrated cellular response to hypoxia requires the concerted action of several O2 sensing mechanism and/or several effectors. The current picture regarding the molecular nature and the role of oxygen-sensitive ion channels in carotid body chemoreceptor cells physiology perfectly exemplify these new concepts.