Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS). Glutamate binds to and activates receptors coupled to both ligand-gated ion channels (ionotropic) and G proteins (metabotropic). The ionotropic glutamate receptors are permeable to cations, including Ca2+, whereas metabotropic glutamate receptors can trigger the release of Ca2+ from intracellular stores. Therefore the activation of glutamate receptors can increase cytoplasmic Ca2+ levels, resulting in the activation of a variety of Ca2+-dependent processes. An increase in intracellular Ca2+ in brain cells is potentially neurotoxic and has been linked to many neurodegenerative disorders and neuronal cell death. Antagonists of glutamate-receptor channels have previously been shown to reduce the neurotoxic damage in a variety of animal models of neurological disorders. Because of the link between glutamate receptors, Ca2+ signaling, and neuronal death, elucidating the molecular mechanistic details of these processes will be crucial to understanding the pathology of various neurodegenerative diseases.