Our principal findings are: (1) CX3CR1 is unregulated in ischemic neurons in vitro and in a mouse model of permanent focal ischemia; (2) neuronal CX3CR1 elevation is associated with apoptotic neuronal death; (3) CX3CR1 deficiency protects mice from ischemic brain damage in vivo; (4) CX3CR1 deficiency reduces glutamate-mediated excitotoxicity in hippocampal neurons cultured in vitro with a mechanism dependent on intracellular calcium. Here, CX3CR1 is linked to ischemia.