Until recently, our understanding of the cellular and subcellular changes evoked by diffuse traumatic brain injury has been framed in the context of primary focal injury. In this regard, the ensuing cell death cascades were linked to contusional-mediated changes associated with frank hemorrhage and ischemia, and these were assumed to contribute to the observed apoptotic and necrotic neuronal death. Little consideration was given to the potential that other non-contusional cell death cascades could have been triggered by the diffuse mechanical forces of injury. While the importance of these classical, contusion-related apoptotic and necrotic cell death cascades cannot be discounted with diffuse injury, more recent information suggests that the mechanical force of injury itself can diffusely porate the neuronal plasmalemma and its axolemmal membranes, evoking other forms of cellular response that can contribute to cell injury or death. In this regard, the duration of the membrane alteration appears to be a dependent factor, with enduring membrane change, potentially leading to irreversible damage, whereas more transient membrane perturbation can be followed by cell membrane resealing associated with recovery and/or adaptive change. With more enduring mechanical membrane perturbation, it appears that some of the traditional death cascades involving the activation of cysteine proteases are at work. Equally important, non-traditional pathways involving the lysosomal dependent release of hydrolytic enzymes may also be players in the ensuing neuronal death. These mechanically related factors that directly impact upon the neuronal somata may also be influenced by concomitant and/or secondary axotomy-mediated responses. This axonal injury, although once thought to involve a singular intraaxonal response to injury, is now known to be more complex, reflecting differential responses to injuries of varying severity. Moreover, it now appears that fiber size and type may also influence the axon's reaction to injury. In sum, this review explicates the complexity of the cellular and subcellular responses evoked by diffuse traumatic brain injury in both the neuronal somata and its axonal appendages. This review further illustrates that our once simplistic views framed by evidence based upon contusional and/or ischemic change do not fully explain the complex repertoire of change evoked by diffuse traumatic brain injury.