In recent years, alterations in the transmission through glutamatergic circuits and changes in glutamate signaling have been proposed to play a key role in the neurochemical disruptions underlying schizophrenia. In particular, the similarities between the symptoms of schizophrenia and the psychotomimetic effects of non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine have spurred interest in the possibility that an NMDA receptor hypofunctional state might underlie schizophrenia. A number of recent studies raise the possibility that agents that selectively increase NMDA receptor function while maintaining activity dependence of activation of the NMDA receptor may be useful in treatment of schizophrenia and other disorders that involve cognitive dysfunction. Inhibitors of the glycine transporter GlyT1 may provide a excellent approach for increasing NMDA receptor activation by increasing availability of glycine, which is a necessary co-agonist of this receptor. Also, two G-protein-coupled receptors, M1 muscarinic receptors and mGluR5 metabotropic glutamate receptors that modulate the NMDA receptor, are potential targets for the development of novel compounds that could ameliorate the symptoms of schizophrenia.