Traumatic brain injury (TBI) is a substantial public health problem. The discovery of progressive, ongoing damage to the brain by means of complex molecular mechanisms which follow the initial injury has raised the possibility of targeted therapeutic intervention. Despite a substantial investment in trials testing dozens of therapeutics in humans, however, to date none has demonstrated robust efficacy. Deficiencies in the design of human clinical trials is likely to explain many translational failures, at least in part. Here we review secondary injury mediators and key trials which have targeted them. We provide a thorough discussion of putative reasons why trials thus far have failed and suggestions for the design of future clinical studies. Important insights from the IMPACT study are also presented in detail; in addition to providing critical insights for future trial design and analysis it suggests that reanalysis of completed studies may reveal inappropriately discarded treatments. Unfortunately limited resources are available for translational research and it is difficult to procure funds needed for well-resourced, large and definitive studies. History suggests, however, that investing in studies that are unlikely to provide a definitive answer only serves to increase required investment as they tend to mandate further study.