The fact that traumatic brain injury is the leading cause of death and disability in the most active population (< 45 years of age) of industrialised countries underscores the need for intensified efforts to define and implement effective neuroprotective strategies. However, despite progressively growing knowledge on the mechanisms involved in the pathobiology of traumatic brain injury and promising preclinical findings, most of the neuroprotection trials have failed to deliver the expected level of beneficial effects. Some of the possible reasons underlying the lack of success of these clinical trials are addressed in this review, which describes some of the most promising and/or controversial ongoing clinical trials from their pathophysiological basis. In addition, new neurobiological findings and their consequence for novel neuroprotective approaches are discussed.