An important feature of traumatic brain injury is that much of the ultimate damage appears to occur in a delayed or secondary fashion. Although the exact timing of these secondary sequelae has yet to be elucidated, recent experimental evidence suggests that an extended window of opportunity exists during which various forms of therapy appear to be efficacious. Moreover, new therapies have been developed which can be targeted at distinct pathophysiologic aspects of brain trauma. This article summarizes recent efforts to define secondary mechanisms of brain trauma and review the development of therapeutic strategies for reversing these deleterious events.