Hypoxia and cerebral ischemia are activators of neurogenesis in the adult mammalian central nervous system. Vascular endothelial growth factor (VEGF) is a hypoxia-inducible angiogenic and neuroprotective growth factor that can promote neurogenesis. In the present study we produced permanent focal cerebral ischemia in transgenic mice that overexpress VEGF (V1). V1 mice showed markedly increased subventricular zone (SVZ) neurogenesis, chains of neuroblasts extending from the SVZ to the peri-infarct cortex, and an increase in the number of newly generated cortical neurons at 14-28 days after ischemia. In concert with these effects, VEGF overexpression reduced infarct volume and improved postischemic motor function. Furthermore, neural stem cells isolated from the SVZ zone of V1 mice expanded and differentiated more rapidly in vitro. VEGF overexpression also protected stem cells against apoptosis by an Akt/PI3-kinase dependent mechanism. Therefore, we propose that VEGF acts as a trophic factor for neural stem cells in vitro and induces sustained neurogenesis in the adult nervous system after cerebral ischemia in vivo. Our data suggest that in addition to its neuroprotective effects, which are associated with improved outcome in the acute phase after cerebral ischemia, VEGF enhances postischemic neurogenesis, which could provide a therapeutic target for more chronic brain repair.