Glutamate regulates the function of central nervous system (CNS), in part, through the cAMP and/or IP3/DAG second messenger-associated metabotropic glutamate receptors (mGluRs). The mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) has been extensively used to elucidate potential physiological and pathophysiological functions of mGluR5. Unfortunately, recent evidence indicates significant non-specific actions of MPEP, including inhibition of NMDA receptors. In contrast, in vivo and in vitro characterization of the newer mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) indicates that it is more highly selective for mGluR5 over mGluR1, has no effect on other mGluR subtypes, and has fewer off-target effects than MPEP. This article reviews literature on both of these mGluR5 antagonists, which suggests their possible utility in neurodegeneration, addiction, anxiety and pain management.