Objectives: Atypical antipsychotics are increasingly being prescribed for the treatment of mood disorders, often off-label. This review describes existing published literature on the efficacy and safety of antipsychotics for the treatment of major depressive disorder (MDD) in adults and adolescents. We discuss current clinical considerations: role as monotherapy, adjunctive, or augmentation therapy, side effect profiles, and optimal dose and duration of therapy. Potential areas for future research and methodological considerations are also highlighted. Method: We conducted a literature search of MEDLINE, EMBASE, PsycINFO, and Cochrane databases. Relevant articles and references were identified. MDD practice guidelines for adolescents and adults were reviewed. Results: Evidence for using atypical antipsychotics to treat MDD is heterogeneous. It is thus difficult to draw firm conclusions regarding their role in therapy. Most current guidelines do not include recommendations for atypical antipsychotics, but off-label use is common in clinical practice. Primary use is adjunct or augmentation therapy for treatment resistant depression. Potential benefits versus side effects must be cautiously considered, especially for children and adolescents. Clinicians must rely on their clinical experience and professional judgment to determine an optimal dose and duration of therapy. Conclusions: There is progressive research to support the use of atypical antipsychotics to treat MDD in adults. However, additional research and well-designed studies are needed to determine the appropriate and safe use of atypical antipsychotics for treating child and adolescent depression. Other subpopulations that may benefit from combination therapy, such as individuals with dual diagnoses, may be identified through future research.