Laboratory studies have identified numerous potential therapeutic interventions that might have clinical application for the treatment of human traumatic brain injury. Many of these therapies have progressed into human clinical trials in severe traumatic brain injury. Numerous trials have been completed, and many others have been prematurely terminated or are currently in various phases of testing. The results of the completed Phase III trials have been generally disappointing, compared with the expectations produced by the successes of these interventions in animal laboratory studies. In this review, we summarize the current status of human traumatic brain injury clinical trials, as well as the animal laboratory studies that led to some of these trials. We summarize criteria for conducting clinical trials in severe traumatic brain injury, with suggestions for future improvements. We also attempt to identify factors that might contribute to the discrepancies between animal and human trials, and we propose recommendations that could help investigators avoid certain pitfalls in future clinical trials in traumatic brain injury.