As many as 29% to 46% of patients with major depressive disorder (MDD) show only partial or no response to an adequate course of an antidepressant. The current practice is to increase the dose, switch to another antidepressant, or to combine the initial antidepressant with an antidepressant of a different class or a non-antidepressant agent. A growing number of studies have also been directed toward exploring the potential use of augmenting traditional antidepressants with nonpharmaceutic supplements, or even using such supplements as monotherapy for depression. S-adenosyl-methionine (SAMe) is one such compound. Compared with many other nonpharmaceutic supplements, SAMe has been extensively studied, and impressive literature extending back three decades suggests the antidepressant efficacy of SAMe. In the present work, the authors summarize the literature, focusing on the potential role of SAMe and its precursors in the pathophysiology of MDD, followed by a review of studies examining the use of SAMe for the treatment of MDD. Finally, the authors propose a model that would explain the actions of SAMe in the central nervous system.