Hyperbaric (HBO) or normobaric oxygen (NBO) therapy applied in acute ischemic stroke aims to increase oxygen supply to the ischemic tissue and to reduce the extent of irreversible tissue damage. Over the past decade, multiple studies have clarified the potential and limitations of oxygen therapy in preclinical stroke models. Considering that the reduction of the infarct size amounts to 30-40%, the cerebroprotection induced by HBO is moderate. In the experimental setting, the effective time window of HBO initiation is only a few hours. Higher pressures (2.5-3 ATA) are more effective. Even though oxygen therapy has some effectiveness in permanent cerebral ischemia without vascular recanalization, it appears more promising for bridging of a transient ischemic period until reperfusion of the penumbra takes place. Compared to HBO, the implementation of NBO to the clinical setting would be substantially less demanding. Although recent experimental NBO-studies are promising, significant effectiveness of NBO was only shown in transient cerebral ischemia and if started within a narrow time window of maximum 30 minutes. Some studies suggest that the effect of HBO is superior to NBO both during transient and permanent cerebral ischemia, even if treatment initiation is delayed. Limited experimental studies do not support an additive effect of a sequential combination of both therapies at present. While the therapeutic potential of oxygen therapy in ischemic stroke was considerably better defined over the past years, the underlying cerebroprotective mechanisms of oxygen therapy remain to be fully elucidated. Recent studies have demonstrated that physical oxygen therapy indeed improves oxygen supply of the ischemic penumbra as well as the cellular bioenergetic metabolism. Therefore, the mitochondria including their role in apoptotic cell death pathways as well as the modification of the cellular hypoxia sensor HIF-1alpha are considered as potential "downstream pathways" of oxygen therapy. Finally, its beneficial effects on the ischemic microcirculation suggest an important modification of various cell types within the neurovascular unit.