Allosteric modulators of metabotropic glutamate receptor subtype 5 (mGluR5) have been developed for their therapeutic potential in a variety of disorders including schizophrenia, drug abuse, fragile X syndrome and anxiety. Modulation of the receptor through an allosteric mechanism provides a high degree of selectivity and avoids many of the pitfalls that are associated with direct acting ligands, such as receptor desensitization. Drug discovery activities in this field have advanced rapidly in recent years, with the development of lead compounds often being accelerated through a variety of novel technologies. The promising effects observed for allosteric modulators of mGluR5 in preclinical studies suggest that their continued development may provide therapeutic options for a range of psychiatric and neurological disorders.