A significant proportion of depressed patients eventually present with treatment‐resistant/refractory major depression (TRD), a debilitating condition that imposes significant health, social, and economic burdens. Recently, a growing level of consensus has been reached on the general meaning of TRD, according to which, depression is considered resistant when at least two trials with antidepressants from different pharmacologic classes (adequate in terms of dose, duration, outcome, and compliance) failed to achieve clinical remission. Regarding the management of TRD, a two‐step approach is suggested, involving first the evaluation of factors that may contribute to treatment nonresponse (such as comorbid medical and psychiatric conditions), and second, the use of the four classical strategies for enhancing antidepressant efficacy (namely optimization, augmentation, combination, and switching). Finally, future research on TRD should include studies addressing, among other issues, the validity of the proposed definitional criteria, the evaluation of reliable predictors of treatment outcome, and the development of novel therapeutic strategies.