N-Methyl-D-aspartate receptors (NMDARs) play vital roles in the central nervous system, as they are primary mediators of Ca(2+) influx during synaptic activity. The subunits that compose NMDARs share similar topological structures but are distinct in distribution and pharmacological properties, as well as physiological and pathological functions, which make the NMDAR one of the most complex and elusive ionotropic glutamate receptors. In this review, we focus on GluN2A and GluN2B, the primary NMDAR subunits in the cortex and hippocampus, and discuss their differences in developmental expression, brain distribution, trafficking, and functional properties during neuronal activity.