Alcohol abuse and dependence constitutes a significant societal and global burden; however, the basic scientific knowledge underlying the development and maintenance of alcohol dependence is limited, resulting in few pharmacotherapies and high rates of relapse following abstinence. A growing body of evidence supports an interaction between ethanol (EtOH) and N-methyl-D-aspartate receptors (NMDARs) in mediating the acute and chronic effects of EtOH. The aim of this review is to synthesize the current knowledge of this interaction on the molecular, cellular and behavioral levels and highlight possible avenues for pharmacotherapeutic treatments.