ABSTRACT: Electron microscopic immunogold analyses have revealed a highly differentiated arrangement of glutamate receptors at excitatory synapses in the central nervous system. Studies focused on the hippocampus and cerebellum have shown that the postsynaptic specialization is the preferential site of NMDA and AMPA receptor expression, and that the δ2 receptor is similarly concentrated at this site. In cases of colocalization (AMPA and NMDA, or AMPA and δ2) the two receptor types appear to be intermingled rather than segregated to separate parts of the membrane. The different groups of metabotropic receptor exhibit distinct distributions at the synapse: group I receptors occur in membrane domains lateral to the postsynaptic specialization; group II receptors are expressed in preterminal membranes or extra-synaptically; whereas group III receptors are found in, or close to, the presynaptic active zone consistent with their roles as autoreceptors. The differentiated distribution of glutamate receptors reflects their functional heterogeneity and explains why some receptors are activated only at high firing frequencies.