Although it is not without controversy, recent preclinical and clinical studies suggest that activation of metabotropic glutamate 2 (mGlu2) receptors by orthosteric mGlu2/3 receptor agonists or allosteric mGlu2 receptor agonists represents a potential new approach to treat schizophrenia and other psychotic disorders. Using rodent models of psychosis, it has been shown recently that expression of the serotonin 5-HT2A receptor is at least in part necessary for the mGlu2-dependent antipsychotic-like behavioral effects of the mGlu2/3 receptor agonist LY379268. Additionally, chronic treatment with atypical antipsychotic drugs epigenetically represses the promoter activity of the mGlu2 (Grm2) gene in mouse and human frontal cortex through a molecular mechanism that requires 5-HT2A receptor-dependent signaling. In the present book chapter, we describe the basic signaling and epigenetic mechanisms whereby serotonin and glutamate system cross talk through these two neurotransmitter receptors and discuss some of the molecular underpinnings of this framework, ranging from pharmacological interaction and biophysical mechanisms to epigenetic pathways.