Bipolar disorder is commonly accompanied by substantial comorbidity, including high rates of anxiety disorders and also of substance and alcohol-use disorders. This chapter considers evidence-based pharmacotherapy for the three main clinical scenarios-episodes of bipolar depression, manic or mixed episodes, and the prevention of relapse. In new episodes of bipolar depression, the three approaches with the strongest evidence base at present are the use of quetiapine, lamotrigine, and the optimization of existing long-term treatments. The evidence for the use of conventional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), in bipolar depression has weakened in recent years. Studies in bipolar disorder have for the most part employed valproate in the form of divalproex. A recentmeta-analysis identified four small randomized placebo-controlled trials of valproate in bipolar I or bipolar II depression. Strong evidence guides first-line choices for episodes of bipolar depression, manic or mixed episodes, and for relapse prevention.