L-glutamate is produced by a great variety of peripheral tissues in both health and disease. Like other components of the glutamatergic system, metabotropic glutamate (mGlu) receptors also have a widespread distribution outside the central nervous system (CNS). In particular, group III mGlu receptors have been recently found in human stomach and colon revealing an extraordinary potential for these receptors in the treatment of peripheral disorders, including gastrointestinal dysfunction. The significance of these findings is that pharmacological tools originally designed for mGlu receptors in the CNS may also be directed towards new disease targets in the periphery. Targeting mGlu receptors can also be beneficial in the treatment of disorders involving central components together with gastrointestinal dysfunction, such as irritable bowel syndrome, which can be co-morbid with anxiety and depression. Conversely, the development of more specific therapeutic approaches for mGlu ligands both centrally as in the gut will depend on the elucidation of tissue-specific elements in mGlu receptor signalling.