Structural neuroimaging and postmortem histopathological studies of the brain have revealed morphological changes in cortical and subcortical regions in individuals diagnosed with depression. Moreover, these regions are known to be functionally altered in mood disorders. This indicates that the morphological changes might be directly involved in the pathophysiology of depression, and implies that antidepressants may be able to regulate or reverse the detected structural abnormalities. Work with animal models has shown that antidepressants are capable of inducing structural alterations in dendrites and axons and changes in the numbers of neural cells. However, there have been no studies in the human brain that have directly addressed whether antidepressant treatment can reverse or regulate the depression-related structural changes. Nevertheless, experience with lithium in bipolar disorder and antipsychotics in schizophrenia suggests that treatment with psychotropic drugs can result in structural changes that are consistent with reversion towards normal values. Clearly, ascertaining the role of the reversal of structural changes in the therapeutic actions of antidepressants will require further longitudinal studies and careful comparisons between those patients with mood disorder who are treated with antidepressants and those who are not.