Traumatic brain injury is a major source of death and disability worldwide. Significant success has been achieved in improving short-term outcomes in severe traumatic brain injury victims; however, there are still great limitations in our ability to return severe traumatic brain injury victims to high levels of functioning. Primary brain injury, due to initial injury forces, causes tissue distortion and destruction in the early postinjury period. Clinical outcomes depend in large part on mediating the bimolecular and cellular changes that occur after the initial injury. These secondary injuries from traumatic brain injury lead to alterations in cell function and propagation of injury through processes such as depolarization, excitotoxicity, disruption of calcium homeostasis, free-radical generation, blood-brain barrier disruption, ischemic injury, edema formation, and intracranial hypertension. The best hope for improving outcome in traumatic brain injury patients is a better understanding of these processes and the development of therapies that can limit secondary brain injury.