To gain better insight into the initiating factors involved in traumatically induced axonal injury cats and rats were subjected to various forms of traumatic brain injury. Following injury at intervals ranging from 10 min. to 3 hours, the animals were sacrificed and prepared in accordance with multiple immunocytochemical strategies capable of detecting focal changes in the axolemma, the subaxolemmal spectrin network, the underlying cytoskeleton as well as any related abnormalities in axoplasmic transport. Through these approaches it was recognized that the most severe forms of injury resulted in focal abnormalities of axonal permeability which were observed together with calpain-mediated spectrin proteolysis in the subaxolemmal network. These events were associated with compaction of the underlying neurofilaments and some microtubular loss which occurred without any direct evidence of overt axoplasmic proteolysis with the exception of the most severely injured fibers. In addition to these severely injured axonal profiles, other injured axons did not manifest overt changes in axolemmal permeability or early calpain-mediated spectrin proteolysis but demonstrated dramatic neurofilament and microtubular misalignment and impaired axoplasmic transport. Lastly, other small caliber axons showed another form of intraaxonal change manifested in the local pooling of organelles in the nodal and paranodal regions, with the suggestion that some of these changes may be reversible. In relation to these axonal responses the efficacy of various therapeutic investigations were assessed. The use of calcium chelators showed a trend for protection in those axons manifesting altered axolemmal permeability. However, the use of early and delayed hypothermia demonstrated dramatic protection resulting in significant reduction in the number of damaged axonal profiles. These studies illustrate the diversity and complexity of those axonal responses evoked by traumatic brain injury, suggesting that multiple forms of therapy may be needed to blunt these multifaceted forms of progression.