The past two decades have witnessed a rise in the 'NMDA receptor hypofunction' hypothesis for schizophrenia, a devastating disorder that affects around 1% of the population worldwide. A variety of presynaptic, postsynaptic, and regulatory proteins involved in glutamatergic signaling have thus been proposed as potential therapeutic targets. This review focuses on positive allosteric modulation of metabotropic glutamate 2 receptors (mGlu2Rs) and discusses how recent preclinical epigenetic data may provide a molecular explanation for the discrepant results of clinical studies, further stimulating the field to exploit the promise of mGlu2R as a target for schizophrenia treatment.