Glu is the most abundant excitatory neurotransmitter in the brain. The first indications that Glu exerted excitatory actions on cerebral cortex were obtained by Hayashi in 1954, and later, observations by Watkin and colleagues showed that Glu can depolarize and excite individual neurons in the cat spinal cord. However, it took the scientific community a long time to realize that Glu was functioning as a neurotransmitter, mainly due to its very high abundance in the brain and its involvement in important metabolic pathways. Full acceptance of the neurotransmitter role of Glu was achieved only with the characterization of selective agonists and antagonists for all Glu receptors (Roberts et al. 1981). The last decade has seen several attempts to exploit the therapeutic potential of Glu receptor ligands since molecular psychiatry and behavioral psychopharmacology have been instrumental in highlighting the possibilities of a pharmacological modulation of Glu in diseases like schizophrenia and treatment-resistant depression (TRD).