Recent evidence suggests that the hippocampus may be disordered in patients with major depressive disorder, with the speculation that disease-associated elevated cortisol levels might mediate alterations in hippocampal physiology and, consequently, alter cognitive performance in persons with the illness. In support of this are reports from several laboratories that have shown a reduction in hippocampal volume in the illness that is most severe in those with early age at onset, many previous episodes, longer durations of untreated illness, and a childhood abuse history. It appears that the posterior segment of the hippocampus is most consistently involved in the volume reduction in patients with major depressive disorder. Cognitive studies show that learning and memory are altered in major depressive disorder, consistent with an abnormality in the posterior hippocampus. Cellular changes in the posterior hippocampus in patients with major depressive disorder have still to be elucidated, but there is evidence of an involvement of an alteration in the serotonin and neurotropin systems. Of interest is that a reduction of mRNA for the serotonin 5-HT1a receptor has been demonstrated in patients with major depressive disorder. It is not clear whether this represents a primary abnormality specific to depression or, alternatively, whether reduced 5-HT1a receptor expression results from abnormal interaction between neurotropins (such as brain-derived neurotrophic factor) and serotonin receptors. Illustrated here is an approach to analyzing volume in the human hippocampus. Using anatomically specific criteria, hippocampal regions of interest were defined on anterior to posterior structural MRI scans (F1). We averaged the volumes for these hippocampal regions of interest across all medication-free depressed patients and contrasted these with matched normal comparison subjects. Consistent with previous data from medicated patients, hippocampal volumes were reduced in persons with major depressive disorder, and these reductions were restricted to the posterior regions (F1). We speculate that this volume reduction represents cellular alterations in 5-HT1a and neurotropin mechanisms, possibly related to elevated cortisol levels.One might consider that these kinds of changes underlie the alterations in learning and memory associated with major depressive disorder.