The associations of folic acid and its derivatives with depressive disorder are reviewed. Derivatives of folic acid such as biopterins and the synthesis of S-adenosyl methionine (SAM) are known either to be associated with improvement or to have a direct therapeutic effect in depressive disorder. Studies investigating plasma and red cell folic acid levels in depressed patients have used differing assay methodologies which make comparison difficult, although there is substantial evidence of the association between depressive disorder (particularly severe depression) and low folic acid levels. The few studies available suggest folic acid has either antidepressant properties or can act as an augmenting agent for standard antidepressant treatment. A recently discovered genetic variant (5,10 MTHFR) leading to altered folic acid metabolism may explain why some individuals are vulnerable to the effects of folic acid deficiency, despite adequate intake. The links of 5,10 MTHFR to the presence of depressive disorder in the community are being investigated. Copyright © 2004 John Wiley & Sons, Ltd.