During both cell differentiation and development, the metabotropic glutamate receptor (mGluR) system plays an important role in securing successful maturation of an organism. Yet, the mGluR system may hold a more crucial role that involves the prevention and reversal of cellular injury during acute and chronic neurodegenerative disorders. As G-protein related receptors, the mGluR system employs a host of signal transduction systems to regulate cell survival and injury. In most circumstances, it is activation of specific mGluR subtypes that prevent the induction of programmed cell death (PCD) along two distinct pathways that involve the degradation of genomic DNA and the exposure of membrane phosphatidylserine (PS) residues. To reach this end of cytoprotection, the mGluR system modulates a selective range of cellular pathways that include protein kinases, intracellular calcium, endonucleases, and cysteine proteases, but excludes more ”up-stream“ cellular mechanisms such as mitogen-activate d protein kinases. Cytoprotection through the mGluR system is directly clinically relevant, since immediate and delayed injury paradigms demonstrate the ability of this system to reverse PCD in both neuronal and vascular cell populations. Future investigations with the mGluR system will offer both a novel and robust foundation for the development of efficacious therapeutic regimens against cellular injury.