Summary l -glutamate is a major excitatory neurotransmitter in the mammalian central nervous system. It acts through ion channel receptors of the AMPA and NMDA subtypes, and selective antagonists acting on these receptors are available. Both in vitro and in vivo animal studies have demonstrated that glutamate antagonists, particularly those acting on the NMDA receptor, can protect neurones against the excitotoxic damage elicited by prolonged exposure to glutamate. In addition, the antagonists can protect neurones against damage in animal models of cerebral ischaemia. Antagonists acting at the AMPA subtype of receptor seem to be most effective in models of global ischaemia, whereas NMDA antagonists are most effective in models involving focal ischaemia. The animal data have prompted clinical trials of NMDA antagonists in the acute treatment of stroke and head injury. The antagonists have not yet been adequately tested in humans to confirm or refute efficacy. Several of the agents which are at present in development have psychotomimetic and cardiovascular side-effects which may limit their clinical utility, although others such as glycine antagonists and intravenous magnesium appear well tolerated. Clinical trials to examine the safety and efficacy of neuroprotective agents need to be very large, and present trials will leave many questions unanswered.