Proinflammatory cytokines, such as IL-1beta, have been implicated in the cellular and behavioral effects of stress and in mood disorders, although the downstream signaling pathways underlying these effects have not been determined. In the present study, we demonstrate a critical role for NF-kappaB signaling in the actions of IL-1beta and stress. Stress inhibition of neurogenesis in the adult hippocampus, which has been implicated in the prodepressive effects of stress, is blocked by administration of an inhibitor of NF-kappaB. Further analysis reveals that stress activates NF-kappaB signaling and decreases proliferation of neural stem-like cells but not early neural progenitor cells in the adult hippocampus. We also find that depressive-like behaviors caused by exposure to chronic stress are mediated by NF-kappaB signaling. Together, these data identify NF-kappaB signaling as a critical mediator of the antineurogenic and behavioral actions of stress and suggest previously undescribed therapeutical targets for depression.