Lithium, carbamazepine, and valproate are widely recognized mood stabilizers. Yet, even when they are used with antidepressants, benzodiazepines, and typical and atypical neuroleptics as needed, there is still a high incidence of lack of response in bipolar illness. Breakthrough days depressed are approximately two and a half times more frequent than days manic and new antidepressant strategies are sorely needed. Lamotrigine looks promising as an antidepressant modality with little switch liability, while gabapentin does not appear to be a antimanic or mood stabilizing agent, but is widely used adjunctively for a variety of comorbid conditions occurring in bipolar illness. Topiramate is promising as a mood stabilizer based solely on open add-on studies, and it also has the positive side effect of weight loss. The atypical antipsychotics are also being widely used in bipolar illness, but their efficacy in depression and long-term prophylaxis has not been adequately expressed and as a class many have the associated liability of weight gain. Thyroid and many other augmentation strategies such as omega-3 fatty acids are also being widely utilized but are based on an inadequate evidentiary database. Within the intramural program of the NIMH, discharge data from the 1970s to 2000 are highly positively correlated to the number of medications on discharge necessary for achieving acute improvement. This has been associated with an earlier age of onset of illness, greater number of prior depressions, and faster cycling patterns in the patients referred over the past three decades. New methodologies are required to evaluate comparative combination strategies and their most optimal development and sequencing.