Retinal ganglion cells are driven by glutamatergic synapses, but they are also very susceptible to glutamate toxicity. Whereas the conventional excitotoxicity model of glutamate-induced cell death requires membrane depolarization, we have found that glutamate toxicity need not be linked with excitation. A large subset of ganglion cells possesses high-affinity kainate receptors that are calcium permeable. At 1–5 μM, kainate produced elevation of internal calcium but did not significantly depolarize ganglion cells. This low concentration of kainate caused ganglion cell death, which could be inhibited by specific kainate receptor antagonists. The toxic effect of kainate may be associated with calcium influx, because toxicity was reduced by polyamines that suppress calcium influx and by an inhibitor of calcium phosphatase. Thus activation of ionotropic glutamate receptors can produce neurotoxicity uncoupled from neuroexcitation.