Acamprosate, in combination with psychosocial therapy, has been shown to be clinically effective in maintaining abstinence in alcohol dependence. Current research suggests that its mechanism of action involves functional antagonism of the ionotropic glutamate N-methyl-d-aspartate (NMDA) receptor. However, direct interactions between acamprosate and the NMDA receptor are weak, and recent findings suggest that acamprosate may modulate NMDA receptors via regulatory polyamine sites, or that it may act directly on metabotropic glutamate receptors. All of these mechanisms are novel for the treatment of alcohol dependence and have far-reaching implications for understanding relapse, as well as for the discovery of drugs with greater efficacy. Understanding the mechanism of action of acamprosate may be an important stimulus for change in the perception and treatment of alcohol dependence.