Reelin, a large protein that regulates neuronal migration during embryonic development, activates a conserved signaling pathway that requires its receptors, very low-density lipoprotein receptor and apolipoprotein E receptor 2, the cytoplasmic adaptor protein Disabled-1 (Dab1), and Src family kinases (SFK). Reelin also markedly enhances long-term potentiation in the adult hippocampus, suggesting that this developmental signaling pathway can physiologically modulate learning and behavior. Here, we show that Reelin can regulate NMDA-type glutamate receptor activity through a mechanism that requires SFKs and Dab1. Reelin mediates tyrosine phosphorylation of and potentiates calcium influx through NMDA receptors in primary wild-type cortical neurons but not in Dab1 knock-out neurons or in cells in which Reelin binding to its receptors is blocked by a receptor antagonist. Inhibition of SFK abolishes Reelin-induced and glutamate-dependent enhancement of calcium influx. We also show that Reelin-induced augmentation of Ca2+entry through NMDA receptors increases phosphorylation and nuclear translocation of the transcription factor cAMP-response element binding protein. Thus, Reelin may physiologically modulate learning and memory by modulating NMDA receptor functions.