The transcription factor CREB has been implicated in signalling pathways relevant for pathogenesis and therapy of depression. CREB is upregulated and activated in the hippocampus by chronic antidepressant treatment, similarly as neurogenesis. Surprisingly, a recent study using CREB-deficient mice also demonstrates an upregulation of neurogenesis correlating with an antidepressant behavioral phenotype.1 Interestingly, CREB-deficient mice show a rapid behavioral response to antidepressants, while wild-type mice do not. This minireview tries to reconcile these new findings with established concepts on CREB, neurogenesis and depression. It also outlines some crucial experiments and lines of future research that could clarify some of the pending questions.