Bipolar depression, the most common phase of bipolar disorder, causes significant morbidity and mortality. Traditional drugs such as lithium, lamotrigine or antidepressants each offer some clinical efficacy; however, efficacy can be limited and side effects are sometimes problematic. Thus there is a major unmet need for effective, well-tolerated agents for the treatment of bipolar depression. The atypical antipsychotics, with their proven efficacy against manic symptoms, are emerging as candidates for use against the depressive phase of bipolar disorder. Several studies have shown that some atypicals improve depressive symptoms in mixed episodes in patients with bipolar disorder; however, few studies have been performed in patients specifically with bipolar depressive episodes. In a randomized, placebo-controlled trial in patients with acute bipolar I depression, olanzapine monotherapy and an olanzapine-fluoxetine combination significantly improved Montgomery-Asberg Depression Rating Scale (MADRS) total scores compared with placebo (p < 0.001) with corresponding effect sizes (improvement of active treatment over placebo divided by pooled standard deviation) of 0.32 and 0.68, respectively. Importantly, there were no significant differences in rates of switch into mania among the three groups. Recent results from an 8-week, randomized placebo-controlled trial in patients with bipolar I and II disorder who were experiencing a bipolar depressive episode showed that quetiapine (300 and 600 mg/day) had significantly greater efficacy compared with placebo in improving the core symptoms of depression, including suicidal thoughts. Quetiapine significantly improved MADRS total scores compared with placebo (p < 0.001); effect sizes (improvement of quetiapine over placebo divided by pooled standard deviation) of 0.66 and 0.80 for 300 and 600 mg/day quetiapine, respectively, were observed. Both doses of quetiapine significantly improved symptoms of anxiety, sleep quality and global quality of life (all, p < 0.001 versus placebo). These initial findings suggest that atypical antipsychotics may prove to be important future treatments for patients with bipolar depression.