The use of atypical antipsychotics is rapidly expanding in the management of bipolar disorder. This therapeutic class appears to have benefits across the spectrum of moods found in bipolar disorder, and a re-examination of the monoamine hypothesis is required. This paper reviews the evidence for the role of monoamines, and particularly dopamine, in bipolar depression and its implications in the treatment of patients, focusing upon the response to atypical antipsychotics. Relevant papers were identified undertaking a literature search using PubMed: preclinical and clinical studies that incriminate the dopaminergic system in bipolar depression, and recent controlled trials supporting the use of atypical antipsychotics, are reviewed. There is substantial evidence indicating that not only serotonin, but also dopamine may still play an important role as a mediator of antidepressant response in bipolar depression. A regionally selective balance between the dopamine and serotonin systems may account for the mood-stabilizing properties of these drugs, and in fact, a low D(2) occupancy might be more relevant to bipolar depression than greater 5-HT(2) action. This mechanism might correlate with the ability to induce neurogenetic effects. Hence, the greater the atypical profile, the more suitable for bipolar depression. Further studies are needed to confirm this hypothesis.