This review explores the role of glutamate excitotoxicity in amyotrophic lateral sclerosis (ALS) and age-related neurodegeneration. ALS is a progressive motor neuron disorder with limited therapeutic options. The study focuses on the cortical hyperexcitability hypothesis, which suggests that increased glutamatergic signaling leads to hyperexcitability and death of motor neurons. Key mechanisms include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased glutamate release, and reduced inhibition by cortical interneurons. Secondary pathways involve mitochondrial dysfunction, reactive oxygen species (ROS) production, and endoplasmic reticulum (ER) stress. Identifying targets in the excitotoxicity cascade is crucial for developing effective therapies. Excitotoxicity is also implicated in other neurodegenerative diseases like Alzheimer's, Huntington's, and Parkinson's. In ALS, factors such as reduced ADAR2 editing of GluR2 subunits and decreased EAAT2 expression contribute to increased calcium influx and excitotoxicity. These processes are linked to the loss of ADAR2 function, TDP-43 pathology, and C9orf72 mutations. Non-cell-autonomous mechanisms, including astrocytic glutamate transporters and microglial activation, also play a role in excitotoxicity. The study highlights the importance of excitotoxicity as a convergent mechanism in ALS and other neurodegenerative diseases. Therapeutic strategies targeting excitotoxic pathways, such as riluzole and edaravone, have shown promise in preclinical models but face challenges in human trials. Understanding the molecular and cellular processes underlying excitotoxicity is essential for developing effective treatments for ALS and related disorders.This review explores the role of glutamate excitotoxicity in amyotrophic lateral sclerosis (ALS) and age-related neurodegeneration. ALS is a progressive motor neuron disorder with limited therapeutic options. The study focuses on the cortical hyperexcitability hypothesis, which suggests that increased glutamatergic signaling leads to hyperexcitability and death of motor neurons. Key mechanisms include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased glutamate release, and reduced inhibition by cortical interneurons. Secondary pathways involve mitochondrial dysfunction, reactive oxygen species (ROS) production, and endoplasmic reticulum (ER) stress. Identifying targets in the excitotoxicity cascade is crucial for developing effective therapies. Excitotoxicity is also implicated in other neurodegenerative diseases like Alzheimer's, Huntington's, and Parkinson's. In ALS, factors such as reduced ADAR2 editing of GluR2 subunits and decreased EAAT2 expression contribute to increased calcium influx and excitotoxicity. These processes are linked to the loss of ADAR2 function, TDP-43 pathology, and C9orf72 mutations. Non-cell-autonomous mechanisms, including astrocytic glutamate transporters and microglial activation, also play a role in excitotoxicity. The study highlights the importance of excitotoxicity as a convergent mechanism in ALS and other neurodegenerative diseases. Therapeutic strategies targeting excitotoxic pathways, such as riluzole and edaravone, have shown promise in preclinical models but face challenges in human trials. Understanding the molecular and cellular processes underlying excitotoxicity is essential for developing effective treatments for ALS and related disorders.