The goal of treatment of depression is full remission, but only a minority of patients will achieve full remission with antidepressant monotherapy. Several forms of augmentation have been found to improve the effect of antidepressants, but in some cases, issues of safety and tolerability may be of concern. Folate in particular has been found to further reduce symptoms in patients with depression when used in conjunction with an antidepressant, and because folate is a water-soluble B vitamin, its safety and tolerability are well established. This strategy would typically be used in patients with low plasma or red blood cell folate levels. Folate augmentation may be used (1) to enhance the efficacy of antidepressants in nonresponders, (2) to enable those who partially respond to antidepressant monotherapy to achieve remission, and (3) to alleviate residual symptoms during antidepressant treatment.