From the therapeutic point of view, the real challenge is not only to improve the symptoms, but to interfere with the pathomechanism of the disease. That is why a considerable interest has recently been devoted to developing glutamate receptor antagonists (mainly of the NMDA type) for acute and chronic neurodegeneration. Developing such a treatment that slows down the progression of the disease is extremely time and cost consuming. At present there is consensus that competitive NMDA receptor antagonists will not find therapeutic applications, in contrast to agents acting at the glycine(B) site, or channel blockers. Recently, at least seven glycine(B) antagonists (e.g. ACEA 1021, GV-150526, GV-196771A, ZD-9379, MRZ 2/576) and over 10 NMDA channel blockers (e.g. Remacemide, ARL-15896AR, HU-211, ADCI, CNS-5161, Neramexane-MRZ 2/579) have been under development, most of them as neuroprotective agents for acute (stroke, trauma) or chronic insult (e.g. Huntington's or Alzheimer's disease). Several substances selective for NR2B NMDA receptor subtypes such as eliprodil, CP-101606 and Ro-25-6981 have been claimed to have a good neuroprotective profile. This presentation is an attempt to critically review preclinical and scarce clinical experience in the development of new NMDA receptor antagonists as neuroprotective agents according to the following scheme: rational, preclinical findings in animal models and finally clinical experience if available. The general impression is that NMDA receptor antagonists may find use in chronic type of neurodegeneration while AMPA antagonists seem to show better promise in acute insult.