Recent hypotheses suggest that depression may involve an inability to mount adaptive structural changes in key neuronal networks. In particular, the addition of new neurons within the hippocampus, a limbic region implicated in mood disorders, is compromised in animal models of depression. Adult hippocampal neurogenesis is also a target for chronic antidepressant treatments, and an increase in adult hippocampal neurogenesis is implicated in the behavioral effects of antidepressants in animal models. The ‘neurogenic’ hypothesis of depression raises the intriguing possibility that hippocampal neurogenesis may contribute to the pathogenesis and treatment of depressive disorders. While there remains substantial debate about the precise relevance of hippocampal neurogenesis to mood disorders, this provocative hypothesis has been the focus of many recent studies. In this review, we discuss the pathways that may mediate the effects of depression models and antidepressants on adult hippocampal neurogenesis, and the promise of these studies in the development of novel antidepressants.