Despite the considerable burden of bipolar depression, the treatment of this debilitating phase of bipolar disorder is suboptimally addressed by currently available pharmacologic options. Consequently, there is a need for the development of new treatment options with enhanced efficacy and tolerability. Evidence of antidepressant efficacy for some of the atypical antipsychotics in the treatment of bipolar depression has recently emerged. The findings of a large-scale, placebo-controlled, double-blind, randomized clinical study of olanzapine alone and in combination with fluoxetine, and a similar study of quetiapine monotherapy, suggest that some of the atypical antipsychotics may be efficacious in treating depressive symptoms in patients with bipolar I disorder. Subpopulation analyses suggest that quetiapine monotherapy and the olanzapine plus fluoxetine combination appear to be effective in treating depression in patients with a rapid-cycling course. The magnitude of improvement in depressive symptoms in the bipolar I population appears to be larger for quetiapine monotherapy compared with either olanzapine or olanzapine plus fluoxetine; however, the limitations of such a cross-study comparison are acknowledged. Both olanzapine monotherapy and combination therapy, as well as quetiapine monotherapy, were well tolerated. The overall incidence of treatment-emergent mania was low and comparable with placebo in both studies. Somnolence, weight gain, increased appetite and nonfasting glucose and cholesterol levels were more commonly reported in patients treated with olanzapine monotherapy or combination therapy compared with placebo. Dry mouth, sedation/somnolence, dizziness, and constipation were more commonly associated with quetiapine treatment. Large, controlled studies are needed to determine whether other psychotropic agents have antidepressant properties that would make them suitable for use in patients with bipolar depression. In addition, direct comparison of the regimens used in the current study should determine whether the differences evident between them can be confirmed.