NMDA receptor (NMDAR) dysfunction has emerged as a common theme in several major nervous system disorders, including ischemic brain injury, chronic neurodegenerative diseases, pain, depression and schizophrenia. Either hyperactivity or hypofunction of NMDARs could contribute to disease pathophysiology. It is likely that distinct subtypes of NMDARs (as defined by subunit composition and/or subsynaptic location) are differentially involved in central nervous system diseases. Here we focus on a few examples of nervous system diseases where the contribution of NMDARs is relatively well characterized and discuss the implications for potential treatment of these illnesses. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.