This review tackles the unresolved issue of the existence of oxygen sensor in the body. The sensor that would respond to changes in tissue oxygen content, possibly along the hypoxia-normoxia-hyperoxia spectrum, rather than to a given level of oxygen, and would translate the response into lung ventilation changes, the major adaptive process. Studies on oxygen sensing, for decades, concentrated around the hypoxic ventilatory response generated mostly by carotid body chemoreceptor cells. Despite gaining a substantial insight into the cellular transduction pathways in carotid chemoreceptors, the exact molecular mechanisms of the chemoreflex have never been conclusively verified. The article briefly sums up the older studies and presents novel theories on oxygen, notably, hypoxia sensing. These theories have to do with the role of transient receptor potential cation TRPA1 channels and brain astrocytes in hypoxia sensing. Although both play a substantial role in shaping the ventilatory response to hypoxia, neither can yet be considered the ultimate sensor of hypoxia. The enigma of oxygen sensing in tissue still remains to be resolved.