The pathophysiological process following traumatic brain injury is extremely complex and not fully understood. Recent developments have further advanced our knowledge of the cellular and molecular mechanisms that cause this damage. The excitotoxic damage, alterations in calcium homeostasis and free radical induced damage are thought to be the key pathways in this process. It is believed that the final target of all these pathways is the mitochondria, through the alteration in the mitochondrial permeability transition pore. Moreover, the inflammatory response may be important in the exacerbation of secondary damage but its exact role is not very well known. Further advances in our understanding of the cellular and molecular mechanisms will be crucial in the design of new therapies that should improve the prognosis of the traumatic brain injury patients.