NOX5 (NADPH oxidase 5) is a calcium-activated transmembrane enzyme that catalyzes the production of superoxide radicals and other reactive oxygen species (ROS) 1. Unlike other NOX family members, NOX5 is uniquely regulated by intracellular calcium binding to its EF-hand domains, which increases NADPH dynamics and permits electron transfer from NADPH to FAD, triggering superoxide production 2. NOX5 lacks the requirement for cytoplasmic regulatory subunits needed by NOX1-3 and is not glycosylated, distinguishing it structurally and functionally from other NOX isoforms 1. The enzyme localizes to perinuclear and endoplasmic reticulum regions, trafficking to the plasma membrane upon activation by vasoactive agents, growth factors, and pro-inflammatory cytokines 1. Physiologically, NOX5 regulates sperm motility, vascular contraction, and lymphocyte differentiation 1. Pathologically, NOX5 hyperactivation contributes to cardiovascular disease, diabetic nephropathy, kidney injury, and cancer through excessive ROS production and oxidative stress 13. Genome-wide association studies identified NOX5 as a blood pressure-associated gene 1, highlighting its clinical significance in hypertension and vascular dysfunction. The recent crystallization of NOX5 structure opens therapeutic opportunities for isoform-specific drug development 1.