The adult brain maintains two regions of neurogenesis from which new neurons are born, migrate to their appropriate location, and become incorporated into the circuitry of the CNS. One of these, the subgranular zone of the hippocampal dentate gyrus, is of primary interest because of the role of this region in learning and memory. We show that mice lacking EphB1, and more profoundly EphB1 and EphB2, have significantly fewer neural progenitors in the hippocampus. Furthermore, other aspects of neurogenesis, such as polarity, cell positioning, and proliferation are disrupted in animals lacking the EphB1 receptor or its cognate ephrin-B3 ligand. Our data strongly suggest that EphB1 and ephrin-B3 cooperatively regulate the proliferation and migration of neural progenitors in the hippocampus and should be added to a short list of candidate target molecules for modulating the production and integration of new neurons as a treatment for neurodegenerative diseases or brain injury.