Stroke is a major cause of death and disability worldwide, with over 700,000 cases annually in the US and 1.5 million deaths in China. Stroke results from complex pathophysiological processes including excitotoxicity, acidotoxicity, ionic imbalance, oxidative/nitrative stress, inflammation, apoptosis, and peri-infarct depolarization. These mechanisms interact and contribute to neuronal and glial cell death. Excitotoxicity, driven by glutamate and NMDA/AMPA receptors, leads to calcium overload and cell death. Acidotoxicity, caused by ischemia-induced acidosis, further exacerbates damage by increasing calcium influx. Inflammation, involving cytokines and toll-like receptors, contributes to tissue damage and neuronal injury. Apoptosis, triggered by oxidative stress and mitochondrial dysfunction, is a key mechanism in the ischemic penumbra. Oxidative and nitrative stress, caused by reactive oxygen species and nitric oxide, leads to DNA damage and cell death. Peri-infarct depolarizations, associated with spreading depression, can worsen ischemic injury. Stroke treatment remains limited, with a focus on reducing reperfusion injury and improving outcomes through combination therapies targeting multiple pathways. Effective stroke therapy likely requires a combinatorial approach, as stroke is a complex and heterogeneous condition. Future research should explore strategies that target multiple mechanisms of ischemic damage to improve neuroprotection and reduce stroke-related disability.Stroke is a major cause of death and disability worldwide, with over 700,000 cases annually in the US and 1.5 million deaths in China. Stroke results from complex pathophysiological processes including excitotoxicity, acidotoxicity, ionic imbalance, oxidative/nitrative stress, inflammation, apoptosis, and peri-infarct depolarization. These mechanisms interact and contribute to neuronal and glial cell death. Excitotoxicity, driven by glutamate and NMDA/AMPA receptors, leads to calcium overload and cell death. Acidotoxicity, caused by ischemia-induced acidosis, further exacerbates damage by increasing calcium influx. Inflammation, involving cytokines and toll-like receptors, contributes to tissue damage and neuronal injury. Apoptosis, triggered by oxidative stress and mitochondrial dysfunction, is a key mechanism in the ischemic penumbra. Oxidative and nitrative stress, caused by reactive oxygen species and nitric oxide, leads to DNA damage and cell death. Peri-infarct depolarizations, associated with spreading depression, can worsen ischemic injury. Stroke treatment remains limited, with a focus on reducing reperfusion injury and improving outcomes through combination therapies targeting multiple pathways. Effective stroke therapy likely requires a combinatorial approach, as stroke is a complex and heterogeneous condition. Future research should explore strategies that target multiple mechanisms of ischemic damage to improve neuroprotection and reduce stroke-related disability.