The effective treatment of depression in people with bipolar disorder remains a clinical challenge. The role of antidepressant medication in treating bipolar depression has been controversial. While early studies and meta-analyses supported a role for antidepressant medication, more recent, high quality randomized controlled trials in bipolar depression have generally not demonstrated efficacy for antidepressant medications. Although the risk of affective switch and long-term de-stabilization remains a concern when using antidepressant medications in bipolar disorder, the magnitude of this risk has been difficult to ascertain with confidence. Maintenance use of antidepressant medication has generally not demonstrated a favorable risk-benefit ratio. Future studies should explore the patient characteristics and response patterns that predict a more favorable response profile to antidepressants amongst patients with bipolar disorder so that the medications can be rationally used in those who are most likely to benefit.