This review focuses on glutamate-mediated excitotoxicity in amyotrophic lateral sclerosis (ALS) and age-related neurodegenerative disorders, emphasizing its role in disease pathogenesis. Excitotoxicity, characterized by increased glutamatergic signaling, leads to motor neuron hyperexcitability and eventual death. The review characterizes both primary and secondary pathways contributing to excitotoxicity, including upregulation of calcium-permeable AMPA receptors, dysfunction of astrocytic glutamate transporters (EAAT2), increased glutamate release from presynaptic terminals, reduced inhibition by cortical interneurons, mitochondrial dysfunction, increased reactive oxygen species (ROS), and endoplasmic reticulum (ER) stress. Key targets in the excitotoxicity cascade are identified, highlighting the importance of this pathway in ALS and suggesting potential therapeutic interventions. The review also discusses the role of excitotoxicity in other neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases, and the potential for excitotoxicity as a common druggable target across these disorders.This review focuses on glutamate-mediated excitotoxicity in amyotrophic lateral sclerosis (ALS) and age-related neurodegenerative disorders, emphasizing its role in disease pathogenesis. Excitotoxicity, characterized by increased glutamatergic signaling, leads to motor neuron hyperexcitability and eventual death. The review characterizes both primary and secondary pathways contributing to excitotoxicity, including upregulation of calcium-permeable AMPA receptors, dysfunction of astrocytic glutamate transporters (EAAT2), increased glutamate release from presynaptic terminals, reduced inhibition by cortical interneurons, mitochondrial dysfunction, increased reactive oxygen species (ROS), and endoplasmic reticulum (ER) stress. Key targets in the excitotoxicity cascade are identified, highlighting the importance of this pathway in ALS and suggesting potential therapeutic interventions. The review also discusses the role of excitotoxicity in other neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases, and the potential for excitotoxicity as a common druggable target across these disorders.