Objective: Atypical antipsychotics (AAPs) have been hypothesized to be beneficial in treatment-resistant depression (TRD). This paper will review a biochemical rationale and will summarize the data regarding the effectiveness of AAPs in TRD. Method: Studies were identified using searches of Pubmed/Medline, EMBase and the Cochrane databases by cross-referencing the term 'depression' with each of the six AAPs. Results: After initial positive, short case reports and clinical trials, larger studies failed to show the effectiveness of AAPs combined with antidepressants for TRD. More recently, larger scale clinical trials have supported the effectiveness of at least some of these medications. While AAPs have gained in popularity for TRD, there are nagging concerns regarding risks such as metabolic syndrome and tardive dyskinesia. Conclusion: The existing research provides some support for the beneficial effects of AAPs when combined with SSRI's in TRD. These medications pose significant risks that must be considered in their use. © 2008 The Authors.