Ischemic injury of cells in the central nervous system is typically set in motion by influx of extracellular Ca(2+). In this issue of Neuron, Stys and colleagues propose that ischemic injury in spinal cord axons is partly the result of ryanodine receptor-mediated release of Ca(2+) from the endoplasmic reticulum (ER), a site of intracellular Ca(2+) storage.