A key role of excitotoxicity in neurodegenerative diseases is being explored and gaining acceptance, but the underlying mechanisms of its participation in neurodegeneration are still uncertain. Excessive activation of glutamate receptors by excitatory amino acids results in a number of deleterious consequences, such as impairment of calcium buffering, free radical generation, activation of the mitochondrial permeability, and secondary excitotoxicity. Dysregulation of glutamate signaling, and calcium homeostasis contribute to excitotoxic neuronal damage in polyQ diseases. Mutant polyQ proteins disrupt calcium signaling pathways, leading to excessive calcium influx into neurons, impaired glutamate clearance, and altered NMDA receptor function, activation of calcium-dependent proteases, excitotoxic neuronal damage, dysfunction and degeneration, dendritic spine loss, neuronal excitability alterations, and neuronal death, particularly in regions of the brain such as the cerebellum and brainstem.