During the past "Decade of the Brain" several neuroprotective agents have been tested in phase III clinical trials for severe head injury (SHI) but unfortunately none of them significantly improved the outcome of these patients. In contrast to the success achieved by these drugs in animal laboratory studies, the results in terms of neuroprotection in the clinical setting have been disappointing. This paper has been divided in three parts: in the first one, we summarize the pathophysiological mechanisms related to SHI, targeted by the neuroprotective agents. In the second part we review the main clinical trials carried out for SHI to date, and in the third one, we analyze the possible reasons that explain why these agents have failed to show efficacy.