The significant economic, social, and emotional costs of depression would bestow much value on a cost-effective nutritional therapy such as supplementation. Recently, a relationship between folate and depression has been observed in clinical studies and inferred from increased understanding of the role of folate in neural mechanisms involved in mood regulation. Current studies suggest that a subpopulation of depressed patients may benefit from treatment with folate supplementation. However, further studies are needed to replicate and extend these findings and to clarify the circumstances under which folate supplementation may effect a role in antidepressant therapy; only then can any routine screening criteria or treatment protocols be established.