Practitioners often assume that antidepressant drugs become a necessary addition to standard mood stabilizers for the treatment of bipolar depression. Yet, the potential value of adding antidepressant medications to mood stabilizers-above and beyond the effects of therapeutically dosed lithium, divalproex, or lamotrigine alone in bipolar I disorder-remains uncertain. This controversy holds particular significance because of the potential for antidepressant drugs to induce manias or worsen the long-term course of bipolar illness by promoting cycle accelerations. In this presentation, controversies will be reviewed regarding the use of single-agent mood stabilizers relative to mood stabilizers combined with antidepressants for both the acute and prophylactic treatment of bipolar depression. Guidelines will be addressed for making best-practice decisions about when to add particular antidepressants to mood stabilizers, alongside issues regarding the optimal duration and safety of antidepressant augmentation of mood stabilizers during the long-term treatment of bipolar disorder.