N-methyl-D-aspartate (NMDA) receptor hypofunction is associated with a range of effects on cognition and behavior in whole animal and human studies. NMDA receptor hypofunction within the brain, which can be induced experimentally in vivo using NMDA receptor antagonist drugs, produces adverse effects on memory function. The results suggest that NMDA receptor hypofunction can preferentially affect neural mechanisms regulating the efficiency of encoding and consolidation into longer-term storage. More pronounced NMDA receptor hypofunction can produce a clinical syndrome that includes core features of psychosis, as well as dissociation. Finally, sustained and severe underexcitation of NMDA receptors in the adult brain is associated with a neurotoxic process with well-characterized neuropathological features. Progressive increases in severity of NMDA receptor hypofunction within the brain can produce a range of effects on brain function, involving local and distributed circuitry, which may underlie the observed changes in behavior. As the brain ages, the NMDA receptor system becomes progressively hypofunctional, potentially contributing to further age-related decreases in memory and learning performance. Pharmacological and genomic methods for preventing NMDA receptor hypofunction, or for preventing the upstream or downstream consequences modeled by treatment with NMDA antagonists, may be applicable to the prevention and treatment of memory and behavioral dysfunction in a variety of neuropsychiatric disease conditions.