The chronic course of bipolar disorder with multiple episodes, persistent symptoms and decreasing function over time has focused on attention on specific targets of mood stabilizers. Of increasing interest are those targets with long term effects and those which are located intracellularly. Multiple effects of these agents on signal transduction pathways have been well established and modulation of these pathways lead to up regulation of several neuroprotective factors. Chronic administration of mood stabilizers in cellular and intact animal models has demonstrated profound neuroprotective effects of these drugs. Microarray studies have elaborated these mechanisms which include several targets involved in energy metabolism such as mitochondrial function and reducing oxidative stress. These targets appear particularly relevant in patients with bipolar disorder since cell loss in prefrontal cortical and limbic regions has been shown in a number of samples of postmortem brain tissue with rather remarkable consistency. There may be subtle changes in the volume of these regions in addition to their function as evidenced by brain imaging studies. Similarly, microarray studies have also identified abnormalities in mitochondrial energy metabolism in postmortem brain tissue from patients with bipolar disorder which are complimentary to those effects of mood stabilizers in animal studies. Together these data suggest that intracellular targets such as those involved in energy metabolism further refine our models of pathophysiology. These findings may lead to the development of novel treatments for bipolar disorder based on previously unidentified mechanisms.