Neuropathic pain, a chronic pain state resulting from peripheral or central nerve injury, can devastate patients' lives and persists long after tissue injury has subsided. Symptoms usually manifest as allodynia and/or hyperalgesia, and current treatments like tricyclic antidepressants and gabapentin show limited efficacy. Glutamate receptor activation, particularly the NMDA subtype, plays a major role in pain induction: prolonged painful stimuli relieve the NMDA receptor from Mg²⁺ block, leading to 'windup' and 'central sensitization' (including upregulation of tyrosine kinase Src). The pursuit of NMDA antagonists for neuropathic pain began in the late 1980s, but many face psychotomimetic 'PCP-like' side effects at effective doses. This review covers competitive antagonists (e.g., CPP, selfotel, perzinfotel) with poor CNS penetration or side effects; noncompetitive ion channel blockers (e.g., ketamine, dextromethorphan, memantine) with mixed clinical results; glycineB site antagonists with ataxia/sedation; and NR2B-selective antagonists (e.g., ifenprodil, traxoprodil) with fewer psychotomimetic effects and ongoing trials. NMDA antagonists may synergize with opiates, but only weak noncompetitive blockers have been tested in humans. Despite mechanistic support and preclinical data, no effective NMDA antagonist for neuropathic pain exists yet; NR2B-selective modulators are promising, and further research on combinations and subtypes is needed.