Ionotropic glutamate receptors - AMPA, kainate and NMDA - are localized to the postsynaptic density and they mediate the majority of excitatory neurotransmission in the central nervous system by opening a transmembrane ion channel upon binding of glutamate. Despite their central role in signal transduction at chemical synapses, the principles of receptor mechanism, grounded on atomic structure of an intact receptor, are not well understood. Early work on the genetically excised agonist binding domain provided a simple model for glutamate-induced activation: agonist binding promotes closure of the clamshell-shaped binding domain. Further studies suggested that these binding domains are assembled as a dimer-of-dimers, a symmetrical arrangement different from the putative 4-fold, tetrameric symmetry of the ion channel domain. How are these different internal symmetries reconciled? To answer this question and to gain insight into the mechanisms of receptor function, we solved the atomic structure of the AMPA-sensitive rat GluA2 receptor complex. The receptor harbors an overall axis of two-fold symmetry and, as foreshadowed by studies on the isolated domains, the extracellular domains are organized as pairs of local dimers, with the ion channel exhibiting four-fold symmetry. The 2-fold (dimeric) and 4-fold (tetrameric) symmetry mismatch between the extracellular and ion channel domains, respectively, is mediated by two pairs of conformationally distinct subunits, A/C and B/D. Remarkably, the manner in which the A/C subunits are coupled to the ion channel gate is different from that of the B/D subunits, with the A/C subunits adopting a conformation distinct from the B/D subunits. The structural studies on glutamate receptors, together with vast knowledge of receptor function and biophysics, now allow us to develop mechanisms of function for AMPA, kainate and NMDA receptors based on three-dimensional, atomic resolution structure.