The roles of the N-methyl-D-aspartate (NMDA) receptor and NMDA receptor-mediated synaptic plasticity are reviewed in the context of depressive disorder and its treatment. The mode of action of antidepressant treatment is poorly understood. Animal studies have suggested that many antidepressant drugs show activity at the NMDA receptor and that NMDA antagonists have antidepressant profiles in preclinical models of depression. A post-mortem study in humans has suggested that certain binding characteristics of the NMDA receptor may be down-regulated in the brains of suicide victims. "Depressogenic" stressors in animals and chronic administration of antidepressant agents perturb NMDA-dependent synaptic plasticity in the hippocampus.