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mGlu receptors are emerging as novel targets for the treatment of ALS.Excitotoxicity is a key player in molecular mechanisms leading to neurodegeneration.mGlu receptors counteract excitotoxicity and induce the production of neurotrophic factors.Pharmacological blockade of mGlu1 and mGlu5 receptors attenuate excitatory neurotransmission.Pharmacological activation of mGlu3 receptors induce the production of neurotrophic factors.Amyotrophic lateral sclerosis (ALS) is a complex genetic, late age-onset, progressive neurodegenerative disorder leading to the death of upper and lower motor neurons. Life expectancy after diagnosis is short due to the ongoing degeneration and to the lack of effective treatments. Axonal alterations, mitochondrial deficits, RNA changes, protein misfolding and turnover, glial dysfunction and hyperexcitability are key players in molecular mechanisms involved in the degeneration of motor neurons. In the context of hyperexcitability, metabotropic glutamate (mGlu) receptors, which are widely distributed throughout the central nervous system and act through many intracellular signaling pathways, are emerging as novel potential drug targets for the therapeutic treatment of ALS, as they are able to counteract excitotoxicity by reducing glutamate release and inducing the production of neurotrophic factors.