Oxidative stress (OS), caused by an imbalance between the generation and detoxification of reactive oxygen and nitrogen species (ROS/RNS), plays a critical role in brain aging, neurodegenerative diseases, and other adverse conditions. While ROS/RNS function as signaling molecules at physiological levels, excessive amounts lead to oxidative modification of proteins, nucleic acids, and lipids, causing dysfunction. Neurons respond differently to OS, with some populations being more vulnerable. These vulnerable neurons are often the first to show functional decline and cell death during aging or in neurodegenerative diseases like Alzheimer's and Parkinson's. Understanding the molecular and cellular mechanisms of selective neuronal vulnerability (SNV) to OS is crucial for developing interventions to protect vulnerable neurons. SNV is characterized by differential sensitivity of neuronal populations to stresses causing cell injury or death. For example, neurons in the entorhinal cortex, hippocampus CA1 region, frontal cortex, and amygdala are particularly vulnerable to Alzheimer's disease. In Parkinson's disease, dopaminergic neurons in the substantia nigra are primarily affected. In amyotrophic lateral sclerosis (ALS), spinal motor neurons are mainly affected. The vulnerability of specific brain regions to various neurodegenerative diseases reflects both the specificity of each disease's etiology and the heterogeneity of neuronal responses to cell-damaging processes. ROS and RNS serve both as stressors and signaling molecules. While excessive ROS/RNS cause oxidative stress, they are also essential for signaling processes such as synaptic plasticity and long-term potentiation (LTP). Neurons differ in their sensitivity to OS due to factors such as high intrinsic OS, high demand for ROS/RNS-based signaling, low ATP production, mitochondrial dysfunction, and high inflammatory response. Other factors, including deficient DNA damage repair, low calcium-buffering capacity, and glutamate excitotoxicity, also contribute to SNV. Neurons in the hippocampus, such as CA1 neurons, are more vulnerable to OS than CA3 neurons. Similarly, cerebellar granule neurons are highly sensitive to OS, leading to significant loss in aged individuals. Dopaminergic neurons in the substantia nigra pars compacta (A9) are more vulnerable to OS than those in the ventral tegmental area (A10). These differences are influenced by factors such as gene expression, mitochondrial function, and calcium regulation. Mitochondrial dysfunction, low ATP levels, and chronic inflammatory responses also contribute to SNV. Glial cells, including astrocytes and microglia, play a role in maintaining CNS homeostasis and can influence neuronal vulnerability through inflammatory responses. Deficient DNA repair, calcium dysregulation, and glutamate hyperactivity further contribute to SNV. These factors collectively explain the selective vulnerability of certain neurons to OS, highlighting the complex interplay between cellular mechanisms and environmental stressors in neurodegenerative processes.Oxidative stress (OS), caused by an imbalance between the generation and detoxification of reactive oxygen and nitrogen species (ROS/RNS), plays a critical role in brain aging, neurodegenerative diseases, and other adverse conditions. While ROS/RNS function as signaling molecules at physiological levels, excessive amounts lead to oxidative modification of proteins, nucleic acids, and lipids, causing dysfunction. Neurons respond differently to OS, with some populations being more vulnerable. These vulnerable neurons are often the first to show functional decline and cell death during aging or in neurodegenerative diseases like Alzheimer's and Parkinson's. Understanding the molecular and cellular mechanisms of selective neuronal vulnerability (SNV) to OS is crucial for developing interventions to protect vulnerable neurons. SNV is characterized by differential sensitivity of neuronal populations to stresses causing cell injury or death. For example, neurons in the entorhinal cortex, hippocampus CA1 region, frontal cortex, and amygdala are particularly vulnerable to Alzheimer's disease. In Parkinson's disease, dopaminergic neurons in the substantia nigra are primarily affected. In amyotrophic lateral sclerosis (ALS), spinal motor neurons are mainly affected. The vulnerability of specific brain regions to various neurodegenerative diseases reflects both the specificity of each disease's etiology and the heterogeneity of neuronal responses to cell-damaging processes. ROS and RNS serve both as stressors and signaling molecules. While excessive ROS/RNS cause oxidative stress, they are also essential for signaling processes such as synaptic plasticity and long-term potentiation (LTP). Neurons differ in their sensitivity to OS due to factors such as high intrinsic OS, high demand for ROS/RNS-based signaling, low ATP production, mitochondrial dysfunction, and high inflammatory response. Other factors, including deficient DNA damage repair, low calcium-buffering capacity, and glutamate excitotoxicity, also contribute to SNV. Neurons in the hippocampus, such as CA1 neurons, are more vulnerable to OS than CA3 neurons. Similarly, cerebellar granule neurons are highly sensitive to OS, leading to significant loss in aged individuals. Dopaminergic neurons in the substantia nigra pars compacta (A9) are more vulnerable to OS than those in the ventral tegmental area (A10). These differences are influenced by factors such as gene expression, mitochondrial function, and calcium regulation. Mitochondrial dysfunction, low ATP levels, and chronic inflammatory responses also contribute to SNV. Glial cells, including astrocytes and microglia, play a role in maintaining CNS homeostasis and can influence neuronal vulnerability through inflammatory responses. Deficient DNA repair, calcium dysregulation, and glutamate hyperactivity further contribute to SNV. These factors collectively explain the selective vulnerability of certain neurons to OS, highlighting the complex interplay between cellular mechanisms and environmental stressors in neurodegenerative processes.