The oxygen therapy is a universal treatment in the hospital setting, especially in the critical care units. The purpose of this therapy is to avoid hypoxemia and to ensure an adequate supply of oxygen to the tissues. But often we overlook the potential adverse effects of oxygen therapy. Oxygen produces lung damage and induces apoptosis and cell death creating an imbalance between the production of reactive species of oxygen and the antioxidant mechanisms. The oxygen therapy inhibits systemic adaptive changes induced by hypoxia, disrupting compensatory mechanisms and causing deleterious effects. We are faced with a challenge in order to treat patients with respiratory failure, counterbalancing hypoxia with hyperoxia-induced damage and introducing therapy lines that are innovative but not risk-free as permissive hypoxemia. Currently many questions remain unresolved and there are not enough clinical studies that validate the therapeutic optimal oxygenation ranges. These ranges may differ depending on each patient and the underlying disease.