Antidepressant monotherapy is used more often than other therapies to achieve symptom remission in depressed patients; however, for patients resistant to antidepressants, other strategies are necessary. Many novel combination therapies have been proposed to treat resistant depression. The efficacy of combination therapies such as lithium augmentation of antidepressants is supported by a large amount of evidence including data from controlled trials. Nonetheless, anecdotal reports suggest that these combinations are underutilized. Data from studies of the use of the combination of atypical antipsychotics and selective serotonin reuptake inhibitors suggest that this is a particularly promising therapeutic avenue. However, more research is needed to corroborate these early results.