A variety of consequences have been ascribed to the activation of NMDA receptors expressed on both the pre- and postsynaptic side of a variety of synapses. The evidence for the expression of postsynaptic NMDA receptors is unequivocal; that for presynaptic receptors is in many cases less direct. Though some findings are difficult to explain without positing the existence of presynaptic NMDA receptors, we find no evidence for their expression. Of particular interest is the involvement of presynaptic NMDA receptors in the induction of spike-timing dependent long term depression in the cerebral cortex between layer 4 spiny stellate cells and layer 2/3 pyramidal cells. Thus far, we suggest that the activation of postsynaptic NMDA receptors are required for this form of plasticity.