 The human brain consumes 20% of total basal oxygen, O2, to support ATP-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, setting the stage for investigators to explore the biochemical basis of oxidative stress in health and disease. This article was authored by James Nathan Kobaly, Maria Luisa Fiorello, and Damian Miles Bailey.