Several authors have recently proposed that excessive calcium (Ca++) influx into postsynaptic cells may be the mechanism by which excitotoxins such as glutamate (Glu), N-methylaspartate (NMA) and kainic acid (KA) cause neuronal necrosis. Here we have undertaken both in vivo and in vitro studies to explore this hypothesis. Our findings indicate that Ca++ does accumulate selectively in neural elements undergoing degeneration in the in vivo mouse hypothalamus following subcutaneous administration of NMA. However, pretreatment with the putative Ca++ channel blocker nimodipine resulted in augmentation rather than suppression of the toxic action of NMA and Glu on the mouse hypothalamus and eliminating Ca++ from the incubation medium did not interfere with the toxic action of Glu, NMA or KA on the chick embryo retina in vitro. We conclude, therefore, that Ca++ influx is an unlikely explanation for excitotoxin-induced degeneration of retinal or hypothalamic neurons.