Ifenprodil and a group of related compounds are selective antagonists of NR2B-containing NMDA receptors. These compounds are antinociceptive in a variety of preclinical pain models and have a much lower side-effect profile compared with other NMDA receptor antagonists. It remains unclear whether the improved safety of these compounds is due to their subtype selectivity or to a unique mode of inhibition of the receptor. Human trials have so far confirmed the good tolerability of these subtype-selective NMDA receptor antagonists; however, whether they are as effective as other NMDA receptor antagonists in pain patients remains to be demonstrated.