Excessive cytosolic calcium ion (Ca²⁺) accumulation during cerebral ischemia triggers neuronal cell death, but the underlying mechanisms are poorly understood. Capacitive Ca²⁺ entry (CCE) is a process whereby depletion of intracellular Ca²⁺ stores causes the activation of plasma membrane Ca²⁺ channels. In nonexcitable cells, CCE is controlled by the endoplasmic reticulum (ER)–resident Ca²⁺ sensor STIM1, whereas the closely related protein STIM2 has been proposed to regulate basal cytosolic and ER Ca²⁺ concentrations and make only a minor contribution to CCE. Here, we show that STIM2, but not STIM1, is essential for CCE and ischemia-induced cytosolic Ca²⁺ accumulation in neurons. Neurons from Stim2^−/− mice showed significantly increased survival under hypoxic conditions compared to neurons from wild-type controls both in culture and in acute hippocampal slice preparations. In vivo, Stim2^−/− mice were markedly protected from neurological damage in a model of focal cerebral ischemia. These results implicate CCE in ischemic neuronal cell death and establish STIM2 as a critical mediator of this process.