A significant proportion of patients with depressive disorders do not experience a full response with antidepressant treatment. Fortunately, most eventually remit, even though the time to response may be significantly delayed in many patients. A variety of options exist to deal with these difficult clinical situations. Established strategies include switching to an antidepressant of an alternative class (e.g., tricyclic to a monoamine oxidase inhibitor [MAOI] or selective serotonin reuptake inhibitor [SSRI]), electroconvulsive therapy (ECT), and augmentation with lithium or thyroid hormone. Promising alternatives include combined serotonin and norepinephrine enhancement strategies (e.g., SSRI plus serotonin norepinephrine reuptake inhibitor [NSRI] or higher doses of venlafaxine or fluoxetine), steroid suppression therapy, augmentation with atypical antipsychotics, and psychotherapy.