Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate glutamatergic neurotransmission, and when pathologically overstimulated induce excitotoxic neuronal death. Of the two families of iGluRs, the non-NMDA receptors have received less experimental attention than the NMDA receptors as mediators of neuronal death in in vitro systems. We have demonstrated that non-NMDA receptor activation is highly lethal for neurons of the chick embryo retina, and further characterize this phenomenon here. Treatment of isolated retinas with any of the non-NMDA receptor agonists glutamate, AMPA, or KA, in the presence of the NMDA receptor antagonist MK-801, led to pathomorphology and cell death. KA was the most effective toxin. All of KA-induced toxicity could be blocked by selective AMPA receptor blockers. The toxicity of both AMPA and glutamate could be greatly increased using cyclothiazide, which blocks AMPA receptor desensitization. These results indicate that KA is the most powerful toxin because it is a non-desensitizing agonist at the AMPA receptors. Glutamate exhibited a paradoxical ability to prevent KA-induced toxicity as measured by a biochemical assay of cell death. Also, histological studies indicated that glutamate selectively blocked KA-induced pathomorphological changes in bipolar cells. This protective effect of glutamate was not mimicked by AMPA, NMDA, or any of several metabotropic receptor agonists, indicating that it may be mediated by a receptor of undescribed pharmacology.