Traumatic brain injury (TBI) is named the most complex disease in the most complex organ in the body. TBI is extremely heterogeneous and so is the underlying pathophysiology. At the time of impact, the primary brain injury results in neuronal, vascular, and glial damage. This primary injury is exacerbated by complex processes leading to progressive brain injury including brain edema and increased intracranial pressure, worsening white matter injury, reduced cerebral blood flow, and a reduced capacity for ATP generation. Furthermore, complex local and systemic inflammatory responses ensue and these may contribute to worsening brain injury. Understanding of the secondary and late injury processes is key in developing novel treatment targets and for correct clinical assessment of the patient. In this chapter, the crucial pathophysiological events occurring in TBI are summarized.