Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) have attracted significant interest in the pharmaceutical industry as potential therapies for a variety of diseases of the CNS. Well-characterized small-molecule mGluR5 NAMs have demonstrated efficacy in several preclinical models of disease, and examples of the clinical efficacy of such NAMs have been reported in recent years. Advances, both in the discovery and development of new small molecules and in the clinical evaluation of known compounds, have been significant in the past 2 years. Recent progress in preclinical drug discovery efforts has used multiple strategies for the discovery of new chemical scaffolds, including the structural modification of known compounds, the rational design of new chemical scaffolds based on known compounds, and the development of screening approaches for new, structurally distinct scaffolds. Progress in the clinical setting with mGluR5 NAMs has also resulted in important recent advances, including the completion of proof-of-concept studies.