Extensive neurogenesis persists in two restricted regions of the adult rodent brain, the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus. In either case, astrocyte-like cells have been proposed to function as stem cells/progenitor cells. The extracellular signaling mechanisms controlling the adult neurogenic pathway are only partially understood. We show that the extracellular nucleotide signaling pathway is associated with adult neurogenesis. SVZ stem cells and hippocampal progenitors in situ both express the nucleoside triphosphate-hydrolyzing ecto-enzyme NTPDase2 and nucleotide receptors (P2 receptors). Neurospheres cultured form the adult SVZ express ecto-nucleotidases as well as P2Y1 and P2Y2 receptors whose activation results in an increase in intracellular calcium and a synergistic augmentation of cell proliferation with the mitogenic growth factors EGF and bFGF. These data support the notion that extracellular nucleotides contribute to the control of adult neurogenesis in both the SVZ and the dentate gyrus.