Treatment-resistant depression (TRD) is a common clinical occurrence among patients treated for major depressive disorder. However, a clear consensus regarding the criteria defining TRD is lacking in the psychiatric community. Many patients who are considered treatment resistant are actually misdiagnosed or inadequately treated. Clinicians need to accurately diagnose TRD by examining primary and secondary (organic) causes of depression and acknowledging paradigm failures that contribute to a misdiagnosis of TRD. A correct determination of what constitutes TRD requires consensus on criteria of treatment response (ie, dose, duration, and compliance) and on the number of adequate trials required before a patient is determined to be nonresponsive. Additionally, clinical validation of available staging models needs to be completed. While several studies have identified predictors of nonresponse, clinical studies investigating the predictors of resistance following the failure of 2 or more antidepressant trials should be pursued. In managing TRD, 3 pharmacotherapy strategies are in clinical use: optimization of antidepressant dose, augmentation/combination therapies, and switching therapies. However, the optimal strategy for treating TRD has yet to be identified. Therefore, further controlled clinical trials are essential to identify the most effective treatment strategies.