Zinc is an essential catalytic or structural element of many proteins, and a signaling messenger that is released by neural activity at many central excitatory synapses. Growing evidence suggests that zinc may also be a key mediator and modulator of the neuronal death associated with transient global ischemia and sustained seizures, as well as perhaps other neurological disease states. Manipulations aimed at reducing extracellular zinc accumulation, or cellular vulnerability to toxic zinc exposure, may provide a novel therapeutic approach toward ameliorating pathological neuronal death in these settings.