Repeated stress induces structural remodeling in brain regions involved with memory and emotions, such as hippocampus, amygdala and prefrontal cortex. Under chronic stress, hippocampal and prefrontal volumes are frequently diminished, whereas the size of the amygdala is increased. Related anatomical changes have been described in patients with bipolar disorder. New data indicate that episodes of depression and mania are associated with decreases neurotrophic and increases in proapoptotic pathways. Such stress- and episode-induced alterations in emotional circuitry may lead to a dysfunctional processing of information, which may render BD patients more vulnerable to subsequent environmental stressors, episodes, and substances of abuse. Allostasis means literally keeping stability through change. Allostatic load refers to the bodily wear and tear that emerges with sustained allostatic states. This concept provides an explanatory link to apparently unrelated findings such as cognitive impairment and higher rates of physical co-morbidity and mortality that occur in the course of bipolar disorder and further highlight the importance of effective long-term prophylaxis.