Current long-term treatment of Parkinson's disease is inadequate, and improved symptomatic and neuroprotective therapies are needed. Recent interest has focused on the use of antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in Parkinson's disease. Abnormally increased activity of the subthalamic nucleus is postulated to play a central pathophysiological role in the signs of Parkinson's disease, and NMDA antagonists may provide a means of decreasing this activity selectively. Like dopaminergic agonists, NMDA antagonists can reverse the akinesia and rigidity associated with monoamine depletion or neuroleptic-induced catalepsy. Very low doses of NMDA antagonists markedly potentiate the therapeutic effects of dopaminergic agonists. There is evidence that the beneficial effects of anticholinergic drugs and amantadine may be mediated, in part, by NMDA receptor blockade. Moreover, NMDA antagonists provide profound protection of dopaminergic neurons of the substantia nigra in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and methamphetamine models of Parkinson's disease. The clinical use of NMDA antagonists may prove useful in Parkinson's disease to treat symptoms and retard disease progression.