The treatment of bipolar depression is one of the most challenging fields in contemporary psychiatry. The best data concern the antipsychotics quetiapine and the olanzapine-fluoxetine combination. However, the usefulness of antidepressants in bipolar depression remains controversial; positive data are available for fluoxetine but negative results have been published for paroxetine. Accumulated knowledge so far suggests that bipolar patients need continuous administration of an antimanic agent even during the acute depressive phase. Although our knowledge is indeed limited, the development of guidelines for polypharmacy is necessary and should be done as soon as possible.