Many aspects of synaptic development, plasticity, and neurotransmission are critically influenced by NMDAtype glutamate receptors (NMDARs). Moreover, dysfunction of NMDARs has been implicated in a broad array of neurological disorders, including schizophrenia, stroke, epilepsy, and neuropathic pain. Classically, NMDARs were thought to be exclusively postsynaptic. However, substantial evidence in the past 10 years demonstrates that NMDARs also exist presynaptically and that presynaptic NMDA receptors (preNMDARs) modulate synapse function and have critical roles in plasticity at many synapses. Here the authors review current knowledge of the role of preNMDARs in synaptic transmission and plasticity, focusing on the neocortex. They discuss the prevalence, function, and development of these receptors, and their potential modification by experience and in brain pathology.