The lifetime prevalence of bipolar disorder (BD) is estimated at 1%−2%, with significant rates of associated impairment in social and occupational functioning (1, 2). Although there have been important advancements in the treatment of BD over the last few decades, most of this work has centered on BD type I, from the management of pure manic or pure depressive episodes to the maintenance of mood stability. In this article we focus on the aspects of BD that are difficult to treat clinically and that lie outside most research to date, but nonetheless represent a significant illness burden: BD II depression and BD depression with mixed features (3). We review the latest evidence-based treatment strategies and recommendations for these conditions, as well as outstanding questions that require further investigation. BD II depression raises considerations distinct from BD I depression; current evidence is strongest for quetiapine in its acute treatment and lithium for long-term maintenance, although significant gaps in our treatment knowledge remain. The appropriate role for antidepressants is still not determined for BD II depression. Similarly, BD depression with mixed features conveys clinical significance distinct from other BD mood episodes, and evidence suggests that antidepressant use should be monitored more closely in this context. Further research is needed to improve our phenomenologic understanding of BD and to increase specificity in treatment approaches.