Excitotoxicity refers to neuronal death caused by the overactivation of excitatory amino acid receptors. Several lines of evidence have linked excitotoxicity to the pathogenesis of both acute and chronic neurologic diseases. Research into the mechanisms of excitotoxic injury has associated activation of excitatory amino acid receptors to free radical generation and nitric oxide, which in turn leads to oxidative stress. Downstream enzymatic effectors include a mix of proteases, free radicals, and endonucleases. Excitatory amino acids play a role in acute neurological diseases such as stroke, trauma, and hypoglycemia; their role in chronic neurological diseases too has been supported by studies using animal models and by work with a glutamate release inhibitor in amyotrophic lateral sclerosis. Chronic diseases linked to excitotoxicity include Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. Despite the overwhelming evidence of excitotoxicity in these acute and chronic diseases and a variety of pharmacological interventions aimed at inhibiting these processes, very few treatments have shown efficacy in clinical trials. As such, recent research has been directed at nonglutamate ion channels responsible for ionic imbalance as well as cross-talk between cell death pathways implicated in excitotoxicity.