Treatment-resistant depression may be due to factors such as co-morbid psychiatric or medical illnesses, chronic psychosocial stresses, and medication nonadherence. Alternative treatment strategies such as optimization, switching to a different antidepressant, augmentation or combination with another antidepressant are strategies useful in such patients. The first strategy in treating resistant depression is to optimize monotherapy. A switch should be made to another agent if there is no response to treatment after an adequate duration. Augmentation and combination strategies are useful if there is sub-optimal response to the initial antidepressant. With several antidepressants (selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors and the newer antidepresssants) and various antidepressant augmentation and combination strategies available to clinicians, the outcome of treating patients with depression should improve.