There is mounting evidence both from experimental and clinical studies that traumatic brain injury (TBI) is associated with a reduction of aerobic metabolism. This results from a variable combination of impaired substrate delivery and mitochondrial failure. Mitochondria, which are responsible for the production of 95% of cell adenosine triphosphate (ATP), may become compromised after TBI. On the other hand, in the very early period after the primary injury, oxygen delivery may be impaired due to arterial hypoxia and/or to a reduction of cerebral blood flow (CBF). As a consequence, 80-90% of patients who die of head injury show ischemia on histo-pathological examination of the brain tissue. In the absence of an appropriate treatment for TBI, these observations favored the hypothesis that manipulation of brain oxygen delivery could be a therapeutic tool to improve aerobic metabolism. Several strategies were developed, including the increase of cerebral perfusion pressure (CPP) using amines or the increase of arterial partial pressure of oxygen (PaO2) through hyperbaric oxygen (HBO) or normobaric hyperoxia. Several experimental and clinical studies, using normobaric hyperoxia, demonstrated an increase in brain tissue oxygen tension and a reduction of brain extracellular lactate levels, but there is no consensus about the biological meaning of these findings. For some authors, they translate an improvement of brain oxidative metabolism, while for others they represent only biological epiphenomena. The current review addresses the rational behind normobaric hyperoxia as a therapeutic application and discusses the experimental and clinical results achieved so far.