Although mood disorders have traditionally been regarded as good prognosis diseases, a growing body of data suggests that the long-term outcome for many patients is often much less favorable than previously thought. Recent morphometric studies have been investigating potential structural brain changes in mood disorders, and there is now evidence from a variety of sources demonstrating significant reductions in regional CNS volume, as well as regional reductions in the numbers and/or sizes of glia and neurons. Furthermore, results from recent clinical and preclinical studies investigating the molecular and cellular targets of mood stabilizers and antidepressants suggest that a reconceptualization about the pathophysiology and optimal long-term treatment of recurrent mood disorders may be warranted. It is proposed that impairments of neuroplasticity and cellular resilience may underlie the pathophysiology of mood disorders, and further that optimal long-term treatment for these severe illnesses may only be achieved by the early and aggressive use of agents with neurotrophic/neuroprotective effects. It is noteworthy that lithium, valproate and antidepressants indirectly regulate a number of factors involved in cell survival pathways including CREB, BDNF, bcl-2 and MAP kinases, and may thus bring about some of their delayed long-term beneficial effects via underappreciated neurotrophic effects. The development of novel treatments which more directly target molecules involved in critical CNS cell survival and cell death pathways have the potential to enhance neuroplasticity and cellular resilience, and thereby modulate the long-term course and trajectory of these devastating illnesses.