Even though in vivo imaging studies document significant reductions of hippocampal volume in depressed patients, the exact underlying cellular mechanisms are unclear. Since stressful life events are associated with an increased risk of developing depression, preclinical studies in which animals are exposed to chronic stress have been used to understand the hippocampal shrinkage in depressed patients. Based on morphometrical studies in these models, parameters like dendritic retraction, suppressed adult neurogenesis and neuronal death, all due to elevated levels of glucocorticoids, have been suggested as major causative factors in hippocampal shrinkage. However, histopathological studies examining hippocampi of depressed individuals have so far failed to confirm either a massive neuronal loss or a suppression of dentate neurogenesis, an event that is notably very rare in adult or elderly humans. In fact, many of the structural changes and the volume reduction appear to be reversible. Clearly, more histopathological studies are needed; especially ones that (a) employ stereological quantification, (b) focus on specific cellular elements and populations, and (c) are performed in nonmedicated depressed patients. We conclude that mainly other factors, like alterations in the somatodendritic, axonal, and synaptic components and putative glial changes are most likely to explain the hippocampal shrinkage in depression, while shifts in fluid balance or changes in the extracellular space cannot be excluded either.