Because of adverse reactions, early efforts to introduce high affinity competitive or use-dependent NMDA receptor antagonists into patients suffering from stroke, head trauma or epilepsy met with failure. Later it was discovered that both low affinity use-dependent NMDA receptor antagonists and compounds with selective affinity for the NR2B receptor subunit met the criteria for safe administration into patients. Furthermore, these low affinity antagonists exhibit significant mechanistic differences from their higher affinity counterparts. Success of the latter is attested to the ability of the following low affinity compounds to be marketed: 1) Cough suppressant - dextromethorphan (available for decades) 2) Parkinsons disease - amantadine, memantine and budipine 3) Dementia - memantine and 4) Epilepsy - felbamate. Moreover, Phase III clinical trials are ongoing with remacemide for epilepsy and Huntingtons disease and head trauma for HU-211. A host of compounds are or were under evaluation for the pos sible treatment of stroke, head trauma, hyperalgesia and various neurodegenerative disorders. Despite the fact that other drugs with associated NMDA receptor mechanisms have reached clinical status, this review focuses only on those competitive and use-dependent NMDA receptor antagonists that reached clinical trails. The ensuing discussions link the in vivo pharmacological investigations that led to the success / mistakes / failures for eventual testing of promising compounds in the clinic.