A sizable proportion of patients suffering from nonpsychotic unipolar depression experience only partial or no clinical response to antidepressant treatment. Switching, augmenting, and combining various pharmaceutical agents can be effective strategies for patients with treatment-resistant depression. The empirical evidence supporting these approaches is inconsistent, however, and there is a paucity of controlled studies to support their efficacy. Additionally, it has been difficult to demonstrate the advantages of these strategies over increasing the dose or duration of the initial drug treatment. This article will review available evidence and clinical considerations regarding switching, augmenting, and combining various agents in the treatment of patients suffering from nonpsychotic unipolar depression who have failed adequate courses of antidepressant treatment. More research is needed that controls for continued time on the initial agent, that compares different strategies, and that determines which patients are the best candidates for which treatment.