The popularity of natural or “alternative” remedies to treat medical and psychiatric disorders has accelerated dramatically over the past decade, in the United States and worldwide. This article reviews the evidence for clinical efficacy, active ingredients, mechanisms of action, recommended dosages, and toxicities of the three best-studied putative natural antidepressants, St. John’s Wort (hypericum), S-adenosyl methionine, and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. Despite growing evidence for efficacy and safety, more comprehensive studies are required before these remedies can be recommended as safe and effective alternatives or adjuncts to conventional psychotropic agents.