Approximately eight out of ten people experiencing a major depressive episode will have one or more further episodes during their lifetime: a recurrent major depressive disorder. Prolongation or lifelong pharmacotherapy has emerged as the main therapeutic tool for preventing relapse in depression. However, outcome after discontinuation of antidepressants does not seem to be affected by the duration of their administration. Loss of clinical effects, despite adequate compliance, has also emerged as a vexing clinical problem. Use of intermittent pharmacotherapy with follow-up visits is another therapeutic option that would leave patients with periods free of drugs and side effects, in consideration of the fact that a high proportion of patients would discontinue the antidepressant anyway. However, the problems of resistance (the fact that a drug treatment may be associated with a diminished chance of response in those patients who successfully responded to it, but discontinued it) and of discontinuation syndromes are a substantial disadvantage of this therapeutic option. In recent years, several controlled trials have suggested that a sequential use of pharmacotherapy in the treatment of the acute episode and psychotherapy in its residual phase may improve long-term outcome. However, patients should be motivated for psychotherapy and skilled therapists should be available. It is important to discuss with the patient the various therapeutic options and to adapt strategies to the specific needs of patients.