Longterm neurological consequences of mild traumatic brain injury and repeated traumatic brain insults, including chronic traumatic encephalopathy (CTE), pose an understandable grave public concern. However, there remains a paucity of knowledge regarding mechanisms of injury linking brain trauma with longterm neurological consequences. In addition, we do not have a way to identify individuals at risk, diagnose the process early, treat the condition, and ultimately prevent it. To fill these knowledge gaps, an integrated approach with parallel animal and human studies to test a comprehensive hypothesis about longterm consequences of traumatic brain insults is needed. I will present such a hypothesis and outline the translatable biomarkers, diagnostic and prognostic indicators of disease progression, and also potential novel therapeutic interventions that might prevent longterm neurological consequences of concussions, repeated traumatic brain insults, and CTE.