In a novel theory, a failure of adult hippocampal neurogenesis has been proposed to provide the biological and cellular basis of major depression. The as yet unresolved function of the new hippocampal neurons will have to be in the center of any attempt to prove this hypothesis. Only knowledge of normal functional relevance of new neurons will allow an assessment of their potential role in disturbed hippocampal function in depression; however, major depression is not primarily a hippocampal disorder. We therefore propose that consideration of the neurogenesis hypothesis of depression be the most prominent aspect of a more general cellular plasticity hypothesis.