Even after optimal treatment with and response to antidepressant medications during acute treatment of major depressive disorder, residual symptoms are common. Patients with residual symptoms are at increased risk of relapse and recurrence. Research suggests that psychotherapy may play an important role in enhancing the effects of antidepressant drug therapy and improving patients' long-term prognosis. Psychotherapy targets specific symptoms associated with relapse (e.g., guilt, hopelessness, negativity, low self-esteem) that antidepressants may not, reduces residual symptoms (e.g., irritability), improves coping skills for long-term disease management and promotes sustained, healthy cognitive changes. In addition, neuroimaging data suggest that psychotherapy and pharmacotherapy target different primary sites of the cortical-limbic pathway with differential top-down and bottom-up effects, resulting in modulation of critical common targets and facilitation of disease remission. The use of adjunctive psychotherapy in the acute phase of depression treatment appears to provide only a modest increase in response rates, although combined pharmaco-psychotherapy may prevent or delay relapse. Simultaneous application of pharmacotherapy and psychotherapy during the maintenance phase does not consistently provide a clear advantage over maintenance pharmacotherapy. In contrast, sequential use of psychotherapy after induction of remission with acute antidepressant drug therapy may confer a better long-term prognosis in terms of preventing relapse or recurrence and, for some patients, may be a viable alternative to maintenance medication therapy.