Clinical recovery after central nervous system (CNS) trauma or ischemia may be limited by a neural injury process that is triggered and perpetuated at the cellular level, rather than by a lesion amenable to surgical repair. It is widely thought that one such process, a fundamental pathological mechanism initiated by CNS injury, is a disruption of cellular Ca2+ homeostasis. Because of the critical role of Ca2+ ions in regulating innumerable cellular functions, this major homeostatic disturbance is thought to trigger neuronal and axonal degeneration and produce clinical disability. We review those aspects of normal and pathological Ca2+ homeostasis in neurons that relate to neurodegeneration and to the application of neuroprotective strategies for the treatment of CNS injury. In particular, we examine the contribution of Ca(2+)-permeable ionic channels, Ca2+ pumps, intracellular Ca2+ stores, intracellular Ca2+ buffering systems, and the roles of secondary, Ca(2+)-dependent processes in neurodegeneration. A number of hypotheses linking Ca2+ ions and Ca2+ permeable channels to neurotoxicity are discussed with an emphasis on strategies for lessening Ca(2+)-related damage. A number of these strategies may have a future role in the treatment of traumatic and ischemic CNS injury.