N-methyl-D-Aspartate (NMDA) type receptors are glutamate-activated calcium channels that play central roles in brain function and disease. Activation of NMDA receptors leads to elevations in synaptic calcium levels, initiating a series of calcium dependent signaling events including activation of nitric oxide synthase and stimulation of calcium/calmodulin dependent protein kinase, and MAP kinase cascades. Through these signal transduction pathways, NMDA receptors mediate both synaptic plasticity and learning and memory. NMDA receptors are composed of multiple subunits. The subunits are thought to co-assemble in different combinations to form functionally distinct NMDA receptors. All receptors contain an NR1 subunit and various numbers of NR2 subunits. NR2b is the major subunit expressed in adult forebrain. NR2 is also a major component of the postsynaptic density in hippocampus and cerebral cortex. The NR1 subunit is encoded by a single gene, which undergoes extensive alternative splicing to generate eight different splice forms. The NR2 subunit class consists of four genes encoding the subunits NR2A-NR2D. In addition to mediating diverse aspects of synaptic physiology, NMDA receptors also play a major role in neurodegenerative diseases. Overactivity of NMDA receptors is implicated in numerous neurodegenerative processes including stroke, Alzheimer’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis.