NMDA receptor (NMDAR) activation is required for many forms of learning and memory as well as sensory system receptive field plasticity, yet the relative contribution of presynaptic and postsynaptic NMDARs over cortical development remains unknown. Here we demonstrate a rapid developmental loss of functional presynaptic NMDARs in the neocortex. Presynaptic NMDARs enhance neurotransmitter release at synapses onto visual cortex pyramidal cells in young mice [before postnatal day 20 (P20)], but they have no apparent effect after the onset of the critical period for receptive field plasticity (>P23). Immunoelectron microscopy revealed that the loss of presynaptic NMDAR function is likely attributable in part to a 50% reduction in the prevalence of presynaptic NMDARs. Coincident with the observed loss of presynaptic NMDAR function, there is an abrupt change in the mechanisms of timing-dependent long-term depression (tLTD). Induction of tLTD before the onset of the critical period requires activation of presynaptic but not postsynaptic NMDARs, whereas the induction of tLTD in older mice requires activation of postsynaptic NMDARs. By demonstrating that both presynaptic and postsynaptic NMDARs contribute to the induction of synaptic plasticity and that their relative roles shift over development, our findings define a novel, and perhaps general, property of synaptic plasticity in emerging cortical circuits.