Xanthine dehydrogenase (XDH) and xanthine oxidase (XOD) are single-gene products that exist in separate but interconvertible forms. XOD utilizes hypoxanthine or xanthine as a substrate and O2 as a cofactor to produce superoxide (·O2 (-)) and uric acid. XDH acts on these same substrates but utilizes NAD as a cofactor to produce NADH instead of ·O2 (-) and uric acid. XOD has been proposed as a source of oxygen radicals in polymorphonuclear, endothelial, epithelial, and connective tissue cells. However, several questions remain about the physiological significance and functions of XOD on aging and oxidative stress. XOD is reported to play an important role in cellular oxidative status, detoxification of aldehydes, oxidative injury in ischemia-reperfusion, and neutrophil mediation. For example, XOD may serve as a messenger or mediator in the activation of neutrophil, T cell, cytokines, or transcription in defense mechanisms rather than as a free radical generator of tissue damage. Emerging evidence on the synergistic interactions of ·O2 (-), a toxic product of XOD and nitric oxide, may be another illustration of XOD involvement in tissue injury and cytotoxicity in an emergent condition such as ischemia or inflammation.