If a patient with major depressive disorder has not responded after an adequate trial of an antidepressant medication, switching to another antidepressant of the same class or a different class may help. When choosing an alternative antidepressant, clinicians should consider the patient's symptoms, drug preferences, and psychiatric and medical comorbidities, as well as drug tolerability, interactions, mechanisms of action, and cost. A wide range of antidepressants is available from a variety of classes, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, tricyclics, and monoamine oxidase inhibitors (MAOIs). From current evidence, it appears that a switch within or between any class is legitimate. When switching between antidepressants, an appropriate switching strategy should be used. Although a sufficient washout period is essential when switching to or from an MAOI, in switches between other classes of antidepressant, no single strategy has proven benefit over another. The direct approach to switching, the crossover approach, the moderate approach, and the conservative approach are all commonly used in clinical practice. Each switch strategy has advantages and disadvantages, and the choice should be made based on the patient, the patient's illness, the medications involved, and clinical judgment.