The majority of clinical trials of N-methyl D-aspartate antagonists have been conducted in the fields of stroke, traumatic brain injury (TBI) and dementia. Stroke and TBI trials have involved more than 9000 patients, but have yielded no therapeutically useful agents, with the possible exception of magnesium for treatment of subarachnoid haemorrhage. Several of the synthetic N-methyl D-aspartate antagonist development programmes have been abandoned owing to concerns about drug toxicity, particularly in stroke. Systematic reviews in stroke and TBI have shown that definitive conclusions cannot be drawn for most agents owing to early termination of trials. In dementia, memantine has shown some benefit in moderate-to-severe Alzheimer’s disease, with no clear benefit to date for milder stages of Alzheimer’s disease or for vascular dementia. Other therapeutic areas of promise remain inadequately explored at present.