Objectives: To review the probable physical, physiologic mechanisms that result in the medical and neuropsychologic complications of diffuse axonal injury (DAI)-associated traumatic brain injury (TBI). Data Sources: Various materials were accessed: MEDLINE, textbooks, scientific presentations, and current ongoing research that has been recently reported. Study Selection: Included were scientific studies involving TBI, particularly direct injury to the axons and glia of the central nervous system (CNS) in both in vitro and in vivo models. These studies include pathologic findings in humans as well as the medical complications and behavioral outcomes of DAI. Studies that addressed animal models of DAI as well as cellular and/or tissue models of neuronal injury were emphasized. The review also covered work on the physical properties of materials involved in the transmission of energy associated with prolonged acceleration-deceleration injuries. Data Extraction: Studies were selected with regard to those that addressed the mechanism of TBI associated with DAI and direct injury to the axon within the CNS. The material was generally the emphasis of the article and was extracted by multiple observers. Studies that correlate the above findings with the clinical picture of DAI were included. Data Synthesis: Concepts were developed by the authors based on the current scientific findings and theories of DAI. The synthesis of these concepts involves expertise in physical science, basic science concepts of cellular injury to the CNS, acute medical indicators of DAI, neuropsychologic indicators of DAI, and rehabilitation outcomes from TBI. Conclusions: The term DAI is a misnomer. It is not a diffuse injury to the whole brain, rather it is predominant in discrete regions of the brain following high-speed, long-duration deceleration injuries. DAI is a consistent feature of TBI from transportation-related injuries as well as some sports injuries. The pathology of DAI in humans is characterized histologically by widespread damage to the axons of the brainstem, parasagittal white matter of the cerebral cortex, corpus callosum, and the gray-white matter junctions of the cerebral cortex. Computed tomography and magnetic resonance imaging scans taken initially after injury are often normal. The deformation of the brain due to plastic flow of the neural structures associated with DAI explains the micropathologic findings, radiologic findings, and medical and neuropsychologic complications from this type of injury mechanism. There is evidence that the types of cellular injury in TBI (DAI, anoxic, contusion, hemorrhagic, perfusion-reperfusion) should be differentiated, as all may involve different receptors and biochemical pathways that impact recovery. These differing mechanisms of cellular injury involving specific biochemical pathways and locations of injury may, in part, explain the lack of success in drug trials to ameliorate TBI. © 2001 American Academy of Physical Medicine and Rehabilitation.