Mitochondrial dysfunction is an important therapeutic target for traumatic brain injury (TBI) and should also be important for the treatment of other acute conditions such as stroke. This chapter discusses mitochondrial bioenergetics and their importance to proper brain function. With a focus on TBI, the importance of mitochondria in cell death pathways initiated by an injury to the central nervous system (CNS) is reviewed. The chapter highlights findings that indicate that phamrmaceutical interventions targeting mitochondria are able to improve histological and functional outcomes following injury in animal models. Brain tissue undergoing the secondary injury cascade following TBI, specifically neuroinflammation, free radical and other reactive species accumulation, and mitochondrial dysfunction, is compromised and at risk for cell death. Pharmacological intervention should, with the right agent(s), minimize this injury cascade and increase tissue sparing and decrease functional deficits, providing a neural substrate for rehabilitation.