Major depressive disorder (MDD) is a chronic, recurrent mental disease that causes serious disability. Because currently available antidepressants have limited efficacy with respect to response and remission in patients with MDD, clinicians must choose the best available treatment interventions for patients who do not respond to initial antidepressant treatment. The existing literature demonstrates that augmentation with atypical antipsychotics (AAs) shows higher response and remission rates compared with antidepressant monotherapy, but is associated with more withdrawals due to adverse events. In this paper, specific clinical issues in the use of AA augmentation for patients with MDD are briefly discussed. Given the limited information and clinical knowledge on the proper and effective use of AAs for MDD, future research should focus on practical clinical issues that can be commonly seen in routine practice but have not been addressed yet. This is because the use of AAs is likely to expand as there is good evidence for their effectiveness and tolerability as augmentation therapy for patients with MDD.