A 1967-1999 MEDLINE search of published reports evaluating the role of the glutamate N-methyl-D-aspartate (NMDA) receptor in pain identified 378 animal studies and 132 human studies. There is convincing evidence in these studies that the NMDA receptor mediates prolonged nociceptive behaviors in animal models and various chronic pain symptoms in the clinical population. Administration of older compounds, such as ketamine, dextromethorphan, and amantadine, which are now known to act as NMDA receptor antagonists, have recently been shown to alleviate chronic pain. For years, the pharmaceutical industry has been attempting to produce novel compounds that modulate NMDA receptor activity; however, the adverse effects associated with this class of drugs have prevented their widespread clinical use. Collaborative studies between basic researchers, clinical scientists, and clinicians are needed to delineate characteristics of NMDA receptor antagonism that predict optimal analgesic activity and an acceptable toxicity profile in patients with chronic pain.