Depression is one on the most common psychological problems encountered in medical practice. Conventional antidepressants, although effective, have many side effects and there is a need for effective medications with fewer side effects.To present all the available clinical evidence on the supplement, S-adenosylmethionine (SAMe) in the treatment of depressive symptoms as well as its safety.Recent clinical studies have revealed that SAMe, a naturally occurring molecule, is safe and effective in the treatment of mild and moderate depression. Although further research is required to clarify SAMe's role as a potential first line treatment for depression, physicians should be aware of the safety and efficacy of SAMe in order to advise patients on its appropriate use as complementary or as an alternative to traditional therapy for depression.