N-methyl-d-aspartate (NMDA) receptor antagonists have therapeutic potential in numerous CNS disorders ranging from acute neurodegeneration (e.g. stroke and trauma), chronic neurodegeneration (e.g. Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, ALS) to symptomatic treatment (e.g. epilepsy, Parkinson’s disease, drug dependence, depression, anxiety and chronic pain). However, many NMDA receptor antagonists also produce highly undesirable side effects at doses within their putative therapeutic range. This has unfortunately led to the conclusion that NMDA receptor antagonism is not a valid therapeutic approach. However, memantine is clearly an uncompetitive NMDA receptor antagonist at therapeutic concentrations achieved in the treatment of dementia and is essentially devoid of such side effects at doses within the therapeutic range. This has been attributed to memantine’s moderate potency and associated rapid, strongly voltage-dependent blocking kinetics. The aim of this review is to summarise preclinical data on memantine supporting its mechanism of action and promising profile in animal models of chronic neurodegenerative diseases. The ultimate purpose is to provide evidence that it is indeed possible to develop clinically well tolerated NMDA receptor antagonists, a fact reflected in the recent interest of several pharmaceutical companies in developing compounds with similar properties to memantine.