Extracellular concentrations of excitatory amino acids increase substantially within cerebral tissue beds exposed to ischaemic conditions. This leads to excessive stimulation of N-methyl-D-aspartate (NMDA) receptors, a major cerebral excitatory neurotransmitter receptor that likely plays a critical role in the propagation of ischaemic injury in neurons. Pharmacological blockade of these receptors has proven to be an effective neuroprotective therapy by a number of animal models of central nervous system ischaemia. Clinical trials of these drugs were begun with high expectations for successful therapy of human stroke. These putative neuroprotective drugs included competitive or non-competitive inhibitors of the NMDA receptor itself, as well as inhibitors of a co-modulatory glycine site. Thus far, all clinical trials of NMDA antagonists have been unsuccessful in establishing benefit for human stroke.