Although the neurobiology of traumatic brain injury (TBI) has been studied more in depth recently as technology has advanced in the field of neuroscience, some of the early seminal papers on the topic that proposed the pathophysiology and the biomechanics of TBI appeared in the early twentieth century. There has been considerable research on understanding the cumulative effects of concussion in terms of the long-term development of neurodegenerative processes that can contribute to a loss in quality of life as an athlete (and/or patient) continues to age. Early experimental studies began to address the relationship between TBI and Alzheimer's disease by focusing on changes in the protein tau. This chapter describes several biochemical, metabolic, and neurochemical processes that may occur after injury. The advent of new and more injury-specific biomarkers, including biofluid and neuroimaging modalities, aids in the diagnosis and treatment of TBI across all levels of the continuum of injury.