Oxygen (O2) is a vital element. Shortage of O2 results in deranged metabolism and important changes in vascular tone with opposite effects on the systemic and pulmonary circulation. During hypoxemia, oxidative stress exposes the organism to a sort of accelerated senescence as well as to several acute untoward effects. Thus, hypoxemia should be promptly recognized and treated, hopefully by measures tailored to the pathophysiological mechanisms underlying hypoxemia. However, O2 therapy remains the most common therapy of hypoxemia, but it must be carefully tailored to relieve hypoxemia without provoking hyperoxia or hypercarbia. Then, the individual response to O2 as well as changing needs of O2 during sleep or exercise must be evaluated to provide the best O2 therapy. Hyperoxia, the effect of overcorrection of hypoxia, can dramatically impact the health status and threaten the survival of the newborn and, through different mechanisms and effects, the adult. A thorough knowledge of the pathophysiological bases of hypoxemia and O2 storage and delivery devices is then mandatory to administer O2 therapy guaranteeing for optimal correction of hypoxemia and minimizing the risk of hyperoxia. Consistent with this aim also is a careful scrutiny of instruments and procedures for monitoring the individual response to O2 over time. Thus, at variance from classical pharmacological therapy, performing O2 therapy requires a vast array of clinical and technical competences. The optimal integration of these competences is needed to optimize O2 therapy on individual bases.