Rehabilitation for acquired brain injury (ABI) has focused largely on alleviation of physical, cognitive, communicative, neurobehavioral, and psychological deficits arising from the injury. Medical stability and functional outcome are dependent on multiple pathophysiological processes beyond metabolic alterations. This chapter addresses multiple factors that have an influence on neuroinflammatory and neurodegenerative processes after ABI. Structural changes associated with acute and chronic Traumatic brain injury (TBI) logically serve as a basis for recovery and potential aging-related conditions. The Blood-Brain Barrier (BBB) is a multicellular structure that segregates the central nervous system (CNS) from the blood flow of the periphery. Inflammation in the brain is typified by microglial activation and the expression of key inflammatory mediators. Neuronal activation of brain regions responsive to stress is associated with microglial activation. Microglial activation is also triggered by beta amyloid protein that results from the cleavage of amyloid precursor protein (APP). Mitochondrial function is crucial to the energy demands of the CNS.