Axon degeneration is a hallmark consequence of chemical neurotoxicant exposure (e.g., acrylamide), mechanical trauma (e.g., nerve transection, spinal cord contusion), deficient perfusion (e.g., ischemia, hypoxia), and inherited neuropathies (e.g., infantile neuroaxonal dystrophy). Regardless of the initiating event, degeneration in the PNS and CNS progresses according to a characteristic sequence of morphological changes. These shared neuropathologic features suggest that subsequent degeneration, although induced by different injury modalities, might evolve via a common mechanism. Studies conducted over the past two decades indicate that Ca2+ accumulation in injured axons has significant neuropathic implications and is a potentially unifying mechanistic event. However, the route of Ca2+ entry and the involvement of other relevant ions (Na+, K+) have not been adequately defined. In this overview, we discuss evidence for reverse operation of the Na+-Ca2+ exchanger as a primary route of Ca2+ entry during axon injury. We propose that diverse injury processes (e.g., axotomy, ischemia, trauma) which culminate in axon degeneration cause an increase in intraaxonal Na+ in conjunction with a loss of K+ and axolemmal depolarization. These conditions favor reverse Na+-Ca2+ exchange operation which promotes damaging extraaxonal Ca2+ entry and subsequent Ca2+-mediated axon degeneration. Deciphering the route of axonal Ca2+ entry is a fundamental step in understanding the pathophysiologic processes induced by chemical neurotoxicants and other types of nerve damage. Moreover, the molecular mechanism of Ca2+ entry can be used as a target for the development of efficacious pharmacotherapies that might be useful in preventing or limiting irreversible axon injury.