The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 (Hollmann and Heinemann, 1994), stimulated this field like no other event since the recognition in the early 1980s that the N-methyl-D-aspartate (NMDA) 2 receptor antagonist, D-AP5, has neuroprotective and anticonvulsant properties (reviewed by Choi, 1998; Dingledine et al., 1990), and that calcium entry through glutamate receptor channels plays important roles in development and in forms of synaptic plasticity that may underlie higher order processes such as learning and memory (Maren and Baudry, 1995; Asztely and Gustafsson, 1996). These earlier findings implicated NMDA receptors in a variety of neurologic disorders that include epilepsy, ischemic brain damage, and, more speculatively, neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases, Huntington’s chorea, and amyotrophic lateral sclerosis. Glutamate receptors are expressed mainly in the central nervous system, but several potentially important exceptions are worth mentioning. The realization that pancreatic islet cells express glutamate receptors that modulate insulin secretion (Inagaki et al., 1995; Weaver et al., 1996, 1998) and that antagonists of NMDA receptors expressed by osteoclasts and osteoblasts slow bone resorption (Chenu et al., 1998; Patton et al., 1998) raise the possibilities that antagonists restricted to the periphery might find uses in the treatment of diabetes and osteoporosis. Moreover, there is evidence for the presence of NMDA and non-NMDA receptors in small, unmyelinated sensory nerve terminals in the skin (Ault and Hildebrand, 1993; Carlton et al., 1995). Subcutaneous injection of as little as 300 pmol of 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) or 30 pmol of MK-801 produced analgesia for a subsequent injection of formalin into the same site. These findings raise the possibility that peripheral glutamate receptors residing on nerve terminals in the skin may be a target for certain forms of pain associated with inflammation. NMDA receptor antagonists can also reduce histamine secretion from mast cells collected from the rat peritoneal cavity (Purcell et al., 1996), and NMDA depolarizes and elevates intracellular Ca2 in mouse taste receptor cells in taste buds (Hayashi et al., 1996). Numerous ionotropic glutamate receptor subunits appear to be expressed by cardiac ganglia, but their functions are unknown (Gill et al., 1998). Thus, the potential therapeutic realm of drugs targeted to glutamate receptors is expanding to include cells (neural and nonneural) in the periphery. Most recently, evidence for a role for ionotropic glutamate receptors expressed by plant cells in light signal transduction has been reported (Lam et al., 1998), suggesting that mammalian receptors may have evolved from a more primitive signaling mechanism. The cloning of the glutamate receptors in the early 1990s has taken the study of glutamate receptor pharmacology, physiology, and pathophysiology to the molecular level. Several major reviews of the initial fruits of cloning appeared in 1994 (Hollmann and Heinemann, 1994; McBain and Mayer, 1994; Nakanishi and Masu, 1994; Gill, 1994). This review focuses primarily on the functional insights and new pharmacological targets identified by molecular biological approaches since 1994. Although synaptic functions of NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been well understood, until recently the physiological roles of …