Patients with treatment-resistant bipolar depression require careful management, which takes into account the life-threatening potential of their depression and the risk of iatrogenic mania. Because there are few data specific to treatment of bipolar depression, much of the approach to bipolar depression is derived from experience with unipolar depression. There are, however, important differences between these two illnesses. Compared with patients with unipolar illness, patients with bipolar depression more likely experience antidepressant benefit from mood-stabilizing medication and, therefore, avoid the risks of antidepressant medication. Treatment of comorbid anxiety and substance abuse improves response. The risk of treating bipolar patients can be reduced but not avoided. Improved outcome may be achieved by careful assessment, prospective mood charting, and attempts to taper antidepressant medications after an appropriate continuation phase.