N-Methyl-D-aspartate (NMDA) is a synthetic chemical binding molecule (ligand) that selectively binds to the “slow response” glutamate NMDA receptor (NMDAR). NMDARs are important for normal brain function and play a central role in learning, memory, and the development of central nervous system hyperactive states. Diverse chemicals belonging to various drug families have demonstrated NMDAR antagonistic effects. Ketamine has been shown to produce antihyperalgesic effects produced by incision and tissue or nerve damage, and has become popular in equine practice as an anesthetic and more recently as an analgesic for standing surgical procedures and the treatment of laminitis. This review focuses on the development of ketamine as an anesthetic and analgesic in horses.