Metabotropic glutamate (mGlu) receptors belong to a class of G-protein linked receptors, which also includes the Ca2+-sensing receptor and the gama-aminobutyric acid (GABAB) receptor. A great variety of drugs has been introduced with the intent of limiting some of the intracellular events that occur downstream of the increase in intracellular Ca2+, including free-radical scavengers, protein kinase C inhibitors, calpain inhibitors, nitric oxide synthase inhibitors, and, lately, caspase inhibitors. Activation of group-II mGlu receptors is neuroprotective in a variety of models, including neuronal cultures, brain slices, and in vivo models of excitotoxicity. The experimental therapy of acute or chronic neurodegenerative disorders can be addressed to the ethiology of the specific disorder, to the pathophysiology of the degenerative process, or to the reparative phenomena with the aim of preventing the cause, slowing or attenuating the progression or reinforcing the function of compensatory neuronal circuitries. Metabotropic glutamate receptors may be considered as a potential target for drugs aimed at reducing the progression of neuronal degeneration.