Major depressive disorder (MDD) is a debilitating and complex psychiatric disorder that involves multiple neural circuits and genetic and non-genetic risk factors. In the quest for elucidating the neurobiological basis of MDD, hippocampal neurogenesis has emerged as a candidate substrate, both for the etiology as well as treatment of MDD. This chapter critiques the advances made in the study of hippocampal neurogenesis as they relate to the neurogenic hypothesis of MDD. While an involvement of neurogenesis in the etiology of depression remains highly speculative, preclinical studies have revealed a novel and previously unrecognized role for hippocampal neurogenesis in mediating some of the behavioral effects of antidepressants. The implications of these findings are discussed to reevaluate the role of hippocampal neurogenesis in MDD.