Abstract In this article, I argue for a reconceptualization of major depressive disorder (major depression) as an infectious disease. I suggest that major depression may result from a parasitic, bacterial, or viral infection and present examples that illustrate possible pathways by which these microorganisms could contribute to the etiology of major depression. I also argue that the reconceptualization of the human body as an ecosystem for these microorganisms and the human genome as a host for non-human exogenous sequences may greatly amplify the opportunity to discover genetic links to the illness. Deliberately speculative, this article is intended to stimulate novel research approaches and expand the circle of researchers taking aim at this vexing illness.