Recent intriguing reports have shown an association between major depression and selective and persistent loss of hippocampal volume, prompting considerable speculation as to its underlying causes. In this paper we focus on the hypothesis that overt hippocampal neuron death could cause this loss and review current knowledge about how hippocampal neurons die during insults. We discuss (a) the trafficking of glutamate and calcium during insults; (b) oxygen radical generation and programmed cell death occurring during insults; (c) neuronal defenses against insults; (d) the role of energy availability in modulating the extent of neuron loss following such insults. The subtypes of depression associated with hippocampal atrophy typically involve significant hypersecretion of glucocorticoids, the adrenal steroids secreted during stress. These steroids have a variety of adverse affects, direct and indirect, in the hippocampus. Thus glucocorticoids may play a contributing role toward neuron death. We further discuss how glucocorticoids cause or exacerbate cellular changes associated with hippocampal neuron loss in the context of the events listed above.