Selective degeneration of pyramidal neurons in regions CA1 and CA3 of the hippocampus is a common structural correlate of several neurodegenerative conditions including Alzheimer's disease, epilepsy and stroke. Several lines of evidence suggest that glutamate, an excitatory neurotransmitter intimately involved in learning and memory processes, may also be involved in hippocampal neurodegeneration. High levels of glutamate are toxic to select groups of pyramidal neurons both in vivo and in vitro and subtoxic levels of glutamate can cause the regression of pyramidal neuron dendrites. In order to determine the basis for this selective vulnerability we employed two rat hippocampal culture paradigms. The first paradigm consisted of neurons isolated from different hippocampal regions (CA1, CA2, CA3, dentate gyrus). Selective vulnerability in the isolated neurons mirrored the selective cell loss that occurs in situ. Dentate granule cells and CA2 pyramidal-like neurons were relatively resistant to glutamate-induced neurodegeneration, while CA1 and CA3 pyramidal neurons were significantly more vulnerable. The second paradigm consisted of sister pyramidal neurons arising from a common progenitor cell. Sister neurons were found to be either both sensitive or both resistant to the degenerative effects of glutamate indicating that mitotic history was an important determinant of selective vulnerability. Experiments which examined the cellular mechanisms underlying selective vulnerability revealed that glutamate caused a large and sustained rise in intracellular calcium levels only in vulnerable neurons. Pharmacological experiments with glutamate receptor antagonists, the inhibitory transmitter GABA, and calcium blockers indicated that vulnerable, but not resistant, neurons expressed glutamate receptors which mediated large rises in intracellular calcium and subsequent degeneration. These results indicate that intrinsic differences in the expression of glutamate receptors linked to calcium influx may account for selective neuronal vulnerability. Treatments which block glutamate receptors, suppress electrical activity, or block calcium channels directly may prove useful in preventing the degeneration of the hippocampal circuitry whose integrity is critical for learning and memory processes.