Recently, there has been a shift in the schizophrenia field focusing on restoring glutamate signaling. Extensive preclinical data suggests that mGlu 5 PAMs could have efficacy in all three symptom domains but there is concern of potential adverse effects. New insights into mechanisms underlying this toxicity may provide a path for discovery of safe mGlu 5 PAMs. Genetic mutations in mGlu 1 have been described in schizophrenics creating interest in this receptor as a therapeutic target. Preclinical data demonstrated the antipsychotic potential of mGlu 2/3 agonists but clinical trials were not successful. However, studies have suggested that mGlu 2 is the subtype mediating antipsychotic effects and selective mGlu 2 PAMs are now in clinical development. Finally, recent genetic studies suggest mGlu 3 modulators may be pro-cognitive.