Over the past three decades, we have learned much about the pathophysiology of brain ischemic injury. Much of this work focused on effects initiated by rapid release of the excitatory neurotransmitter, glutamate, and downstream Ca²⁺ overload. Yet therapeutic interventions based upon these mechanisms have had limited success. More recently, a second divalent cation, Zn²⁺, has garnered considerable attention as a signal ion and mediator of damage in brain ischemia. Zn²⁺ accumulates in damaged neurons after ischemia in many areas of the mammalian forebrain and contributes in diverse ways to the injury process. The past decade has seen rapid advances in our understanding of ways in which Zn²⁺ may contribute to distinct stages of the ischemic neurodegneration cascade. It is hoped that this emerging understanding will suggest new and more effective treatments to decrease morbidity after cerebral ischemia.