Ionotropic glutamate receptors mediate the vast majority of fast excitatory synaptic transmission in the CNS. Elucidating the structure of these proteins is central to understanding their overall function and in the last few years a tremendous amount of knowledge has been gained from the crystal structures of the ligand-binding domains of the receptor protein. These efforts have enabled us to unravel the possible mechanisms of partial agonism, agonist selectivity and desensitization. This review summarizes recent data obtained from structural studies of the binding pockets of the GluR2, GluR5/6, NR1 and NR2A subunits and discusses these studies together with homology modelling and molecular dynamics simulations that have suggested possible binding modes for full and partial agonists as well as antagonists within the binding pocket of various ionotropic glutamate receptor subunits. Comparison of the ligand-binding pockets suggests that the ligand-binding mechanisms may be conserved throughout the glutamate receptor family, although agonist selectivity may be explained by a number of features inherent to the AMPA, kainate and NMDA receptor-binding pockets such as steric occlusion, cavity size and the contribution of water-bridged interactions.