Understanding of the pathophysiology of neuronal injury has advanced remarkably in the last decade. This largely reflects the burgeoning application of molecular techniques to neuronal cell biology. Although there is certainly no consensus hypothesis that explains all aspects of neuronal injury, a number of interesting observations have been published. In this brief review, we examine mechanisms that appear to contribute to the pathophysiology of neuronal injury, including altered Ca2+ signaling, activation of the protease cascades coupled to apoptosis, and mitochondrial deenergization associated with release of cytochrome c, production of free radicals, and oxidative injury. Finally, evidence for neuroprotective mechanisms that may ameliorate cell injury and/or death are reviewed. Little information has been published regarding the mechanisms that mediate injury in the enteric nervous system, necessitating a focus on models outside the gastrointestinal (GI) tract, which may provide insights into enteric nervous system injury.