The article reviews the pathophysiology of ischemic brain damage, which is a devastating condition affecting millions of people annually in the United States and China. Ischemic strokes, which account for 87% of all stroke cases, result from restricted blood flow to the brain, leading to insufficient oxygen and glucose delivery. This triggers multiple pathological processes, including excitotoxicity, acidosis, ionic imbalance, oxidative/nitrative stress, inflammation, apoptosis, and peri-infarct depolarization. The article discusses the complex interplay of these pathways and their therapeutic targets. Excitotoxicity involves the release of glutamate, leading to NMDA and AMPA receptor activation and calcium overload. Acidosis exacerbates excitotoxicity through the activation of ASIC channels. Peri-infarct depolarizations, such as cortical spreading depression, can cause further tissue damage. Oxidative and nitratve stress, driven by mitochondrial dysfunction and increased reactive oxygen species, contribute to neuronal death. Inflammation, involving neutrophils, lymphocytes, and cytokines, also plays a significant role in ischemic brain injury. Apoptosis, often triggered by mild ischemic injury, involves the release of cytochrome c and the activation of caspases. The article concludes that effective stroke therapy may require a combinatorial approach, targeting multiple pathways to maximize neuroprotective effects.The article reviews the pathophysiology of ischemic brain damage, which is a devastating condition affecting millions of people annually in the United States and China. Ischemic strokes, which account for 87% of all stroke cases, result from restricted blood flow to the brain, leading to insufficient oxygen and glucose delivery. This triggers multiple pathological processes, including excitotoxicity, acidosis, ionic imbalance, oxidative/nitrative stress, inflammation, apoptosis, and peri-infarct depolarization. The article discusses the complex interplay of these pathways and their therapeutic targets. Excitotoxicity involves the release of glutamate, leading to NMDA and AMPA receptor activation and calcium overload. Acidosis exacerbates excitotoxicity through the activation of ASIC channels. Peri-infarct depolarizations, such as cortical spreading depression, can cause further tissue damage. Oxidative and nitratve stress, driven by mitochondrial dysfunction and increased reactive oxygen species, contribute to neuronal death. Inflammation, involving neutrophils, lymphocytes, and cytokines, also plays a significant role in ischemic brain injury. Apoptosis, often triggered by mild ischemic injury, involves the release of cytochrome c and the activation of caspases. The article concludes that effective stroke therapy may require a combinatorial approach, targeting multiple pathways to maximize neuroprotective effects.