Our results demonstrated that the neurotoxicity of glutamate and closely related agonists was mediated by the NMDA receptor in rat cerebellar granule cells. Evidence was presented to support our hypothesis that the pivotal event in the transition of these EAAs from neurotransmitters to neurotoxins is relief of the voltage-dependent Mg++ block of the NMDA channel due to changes in membrane potential which can be caused by depletion of highly phosphorylated nucleotides or by other depolarizing stimuli. Persistent stimulation of NMDA receptors whose channels are unblocked by Mg++ can permit excessive influx of Na+ and Ca++ and neuronal death can follow by a mechanism not yet understood. Glutamate is not toxic at kainate receptors although they are present on these cells. These findings underline the potential importance of perturbations in energy metabolism in a variety of neurodegenerative disorders and in the normal process of aging which share the common feature of the loss of neurons.