Metabotropic glutamate receptors (mGluRs) share a common molecular morphology with other G protein- linked receptors, but there expression throughout the mammalian nervous system places these receptors as essential mediators not only for the initial development of an organism, but also for the vital determination of a cells fate during many disorders in the nervous system that include amyotrophic lateral sclerosis, Parkinsons disease, Alzheimers disease, Huntingtons disease, Multiple Sclerosis, epilepsy, trauma, and stroke. Given the ubiquitous distribution of these receptors, the mGluR system impacts upon neuronal, vascular, and glial cell function and is activated by a wide variety of stimuli that includes neurotransmitters, peptides, hormones, growth factors, ions, lipids, and light. Employing signal transduction pathways that can modulate both excitatory and inhibitory responses, the mGluR system drives a spectrum of cellular pathways that involve protein kinases, endonucleases, cellular acidity, energy metabolism, mitochondrial membrane potential, caspases, and specific mitogen-activated protein kinases. Ultimately these pathways can converge to regulate genomic DNA degradation, membrane phosphatidylserine (PS) residue exposure, and inflammatory microglial activation. As we continue to push the envelope for our understanding of this complex and critical family of metabotropic receptors, we should be able to reap enormous benefits for both clinical disease as well as our understanding of basic biology in the nervous system.