Ionotropic glutamate receptors (iGluRs) constitute a family of ligand-gated ion channels mediating fast synaptic transmission in the central nervous system. iGluRs play an important role for the development and function of the nervous system, including learning and memory. However, iGluRs are also implicated in or have causal roles for several brain disorders, and their involvement in neurological diseases has stimulated widespread interest in their structure and function. The first publication in 1998 of the crystal structure of a soluble construct of the ligand-binding domain (LBD) of GluA2 [1] has in the years to come stimulated extensive studies on GluA2 and other iGluR subunits. Crystal structures of wildtype and mutant proteins, combined with functional data, have led to models for receptor activation and desensitization by agonists, inhibition by antagonists and block of desensitization by positive allosteric modulators, as well as provided some understanding of subunit selectivity. In 2009, the crystal structure of the full-length GluA2 receptor was determined to 3.6 Å resolution [2]. A comparison of the full-length GluA2 structure with the GluA2 LBD structure shows that this soluble protein is a good model system of the full length-receptor as the dimeric unit is very similar. Still, the most extensively studied iGluR with regard to crystal structures is GluA2. However, structures are now also available of the LBD of other AMPA receptors, i.e. GluA3 and GluA4, kainate receptors, i.e. GluK1 and GluK2, NMDA receptors GluN1, GluN2A, GluN3A and GluN3B, as well as of the GluD2 receptor. Today, structures are available of an LBD in complex with in total 32 different agonists: 19 agonists with GluA2, 2 with GluA3, 3 with GluA4, 8 with GluK1, 5 with GluK2, 6 with GluN1, 1 with GluN2A, 3 with GluN3A, 2 with GluN3B and 1 with GluD2. These structures have provided information on receptor motifs for recognition of the alpha-amino acid part of the agonist as well as for recognition of the distal part of the agonists. An overlay of structures of all agonist complexes with GluA2 show that the alpha-amino acid moiety of the agonists is essentially located at the same position in the binding site, and it forms the same contacts to GluA2 residues in all structures. This highly underlines the importance of the alpha-amino acid functionality. Much larger variability is seen at the distal sites. Agonists overall adopt two different binding modes in GluA2, characterized as the glutamate-like and AMPA-like binding modes [1]. A special feature in the AMPA binding mode is the presence of an additional water molecule, which tethers the agonist to GluA2. In the glutamate binding mode, a distal oxygen atom of the agonist mimics this additional water molecule seen in the AMPA binding mode. A relationship has been hypothesized to exist between the extent of interaction of the agonist with a hydrophobic pocket and the affinity of some agonists [2]. The GluA2 residue Met708 that takes part in forming this pocket undergoes major side-chain conformational changes (induced fit), to optimize the van der Waals stabilization of the bound agonist. This induced fit allows the hydrophobic pocket to change in size in order to accommodate agonist substituents of various sizes. Binding of agonists to the LBD of iGluRs can be described as a “Venus flytrap” mechanism. In the resting state, the LBD is present in an open form [1]. When an agonist binds to the LBD, a change in conformation occurs, resulting in a closure of the two domains D1 and D2. This domain closure is thought to result in the opening of the ion-channel (receptor activation). The GluA2 LBD can adopt a range of ligand-dependent conformational states, which then control the open probability of discrete subconductance states of the ion channel [4]. An excellent correlation between agonist-induced domain closure of the GluA2 LBD and compound efficacy at GluA2 has been obtained from electrophysiology experiments undertaken on GluA2 receptors, providing evidence that the conformational changes due to domain closure, when propagated to the channel segments, lead to receptor activation. Whereas partial agonists at GluA2 induce intermediate domain closure in the LBD ranging from 13-18 degrees of closure, full agonists lead to full closure of the LBD (20-22 degrees). In conclusion, the structural results together with functional studies have provided important new information on iGluR function at the molecular level, and have and will form powerful platforms for the design of new selective drugs.