To illustrate how recent international initiatives, supported by the National Institutes of Health (NIH) and the Department of Defense, have helped us better understand different aspects of traumatic brain injury (TBI), including the contribution of primary blast overpressure to mild TBI and post-traumatic stress disorder. A broad effort is gaining momentum to unravel reasons behind failed therapeutic trials in TBI.Heterogeneity seems to be one fundamental barrier to successful therapeutic trials in TBI. To compensate for heterogeneity, multiple workgroups were assigned to approach the problem. The International Mission for Prognosis and Clinical Trial design database was generated and used as a medium to adjust for multiple covariates. In addition, sliding dichotomy and proportional odds were applied to statistical methodology in order to improve power calculations. The conference report of Margulies and Hicks proposed combination therapies to add synergy to treatment effects. In October 2007, a workgroup was assigned by the NIH to work on a novel multidimensional classification of TBI, one with a strong pathoanatomical, pathophysiological, and functional congruity. As two international randomized trials on decompressive craniectomy approach completion, an outburst of class II and III studies suggest that this simple surgical procedure may change our future outlook on management of severe head injury.Well designed, targeted, combination therapies based on multidimensional classification of TBI may result in better appreciation of treatment effects in future randomized controlled trials.