PURPOSE OF REVIEW: Translating the efficacy of neuroprotective agents in experimental traumatic brain injury to clinical benefit has proven an extremely complex and, to date, unsuccessful undertaking. The focus of this review is on neuroprotective agents that have recently been evaluated in clinical trials and are currently under clinical evaluation, as well as on those that appear promising and are likely to undergo clinical evaluation in the near future. RECENT FINDINGS: Excitatory neurotransmitter blockage and magnesium have recently been evaluated in phase III clinical trials, but showed no neuroprotective efficacy. Cyclosporin A, erythropoietin, progesterone and bradykinin antagonists are currently under clinical investigation, and appear promising. SUMMARY: Traumatic brain injury is a complex disease, and development of clinically effective neuroprotective agents is a difficult task. Experimental traumatic brain injury has provided numerous promising compounds, but to date these have not been translated into successful clinical trials. Continued research efforts are required to identify and test new neuroprotective agents, to develop a better understanding of the sequential activity of pathophysiologic mechanisms, and to improve the design and analysis of clinical trials, thereby optimizing chances for showing benefit in future clinical trials.