(S)-Glutamic acid (Glu), which is the main excitatory neurotransmitter in the central nervous system (CNS), and other excitatory amino acids (EAAs) operate through four different classes of receptors. In addition to the three heterogeneous classes of ionotropic EAA receptors (iGluRs), named N-methyl-D-aspartic acid (NMDA), (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), and kainic acid (KA) receptors, a heterogeneous class of G-protein coupled EAA receptors (mGluRs) has been shown to have important functions in neuronal signaling processes. It is now generally agreed that iGluRs as well as mGluRs play important roles in the healthy as well as the diseased CNS, and that all subtypes of these receptors are potential targets for therapeutic intervention in a number of diseases. The cloning of the different subunits of the iGluRs and of the eight subtypes of mGluRs represents a major breakthrough. Whereas at present six NMDA receptor subunits (NR1, NR2A-2D, and NR3A) have been cloned and characterized in regards to primary structure, four AMPA receptor subunits (iGluR1-4) have similarly been characterized, and so far five subunit building blocks for KA-preferring receptors (iGluR5-7, KA1, and KA2) have been identified. Most if not all physiological iGluRs have heterotetra- or -pentameric structures, but the number of functional NMDA, AMPA, and KA receptors in the CNS is not known. At present, eight subtypes of the seven transmembrane (7TM) mGluRs have been characterized, but there is evidence to suggest that further subtypes of mGluRs may be identified. These achievements form the basis of the almost explosive increase of research activities in the EAA receptor field. A major goal of these widely ramified molecular biological, physiological, structure/function, and medicinal chemistry approaches is to identify subtype-selective EAA receptor ligands. Such compounds capable of activating, blocking, or modulating iGluRs or mGluRs are essential pharmacological tools, which may be further developed into therapeutically useful drugs. Meanwhile, the search for further subunits of iGluRs and subtypes of mGluRs continues. While new receptor proteins will probably be minor in terms of density and distribution in the CNS, they may constitute EAA receptors involved in the regulation of distinct physiological mechanisms of particular interest in certain disease states.