Disturbances of glutamate-mediated neurotransmission have been implicated in a broad range of nervous system disorders. Numerous attempts to correct nervous system dysfunction by pharmacological intervention at glutamate receptors have been made, and some of the approaches have achieved a high level of preclinical validation. However, in a number of cases involving agents acting as blockers of the ionotropic glutamate receptors, clinical success could not be achieved, mostly because of the lack of a therapeutic window. The identification of the metabotropic glutamate receptor (mGluR) family and their modulatory role in the control of neurotransmission provided a new means to alter glutamatergic transmission. Furthermore, selective agents acting as allosteric antagonists at the mGluR5 subtype have demonstrated therapeutic potential. The identification and characterization of mGluR5 antagonists and recent progress in clinical development are summarized.