 20% of the human brain's oxygen budget is used for ADP-intensive neuronal activity, and oxidative stress can cause neurodegeneration due to various reasons such as unsaturated lipid enrichment, mitochondria, calcium, glutamate, modest antioxidant defense, redox active transition metals, neurotransmitter auto-oxidation, and RNA oxidation. The complex interplay between these factors determines neuronal susceptibility to oxidative stress in a dynamic context and neural identity-dependent manner.