Depression is a major cause of morbidity worldwide and despite a number of treatment options a vast proportion of patients are treatment resistant. Folate and homocysteine have been implicated in the neuropathophysiology of depression; however, its therapeutic implications are still largely unexplored. The need of the hour is to develop a greater understanding about their role in pathogenesis of depression, so that potential preventive and treatment options can be established. This review focuses on previous studies investigating the association between serum levels of folate, homocystiene and depression. The authors suggest that there is strong published evidence for the association between lower levels of serum folate, higher levels of homocysteine and depression; however more prospective studies are required to establish casuality and treatment implications.