In general, the simple concepts first proposed over a decade ago for the role of xanthine oxidase (XO) in pathophysiolgy are no longer sufficient. This review summarizes evidence that has led to a resurgence in interest of XO physiology and pathology and in particular, data that implicates XO and nitric oxide (·NO) in the development of multiple organ dysfunction (MODS) following various pathologic states. The challenge for the next few years will be to define the precise mechanisms that XO plays in normal physiology and pathology. Although it has long been recognized that XO can produce oxidants, the significance of XO-generated oxidants extends beyond the concept of the intracellular generation of cytotoxic oxidants. It has been demonstrated that XO can be released into the circulation from cells and tissues with high intracellular XO specific activity following I/R, sepsis, burns, acute viral infection, and hemorrhagic shock. Once in the plasma the conversion to XO is rapid (< 1 min) and complete. It has been subsequently demonstrated that this circulating XO may bind and concentrate on vascular endothelial cells surfaces, and thereby result in injury to remote tissues with low endogenous XO (e.g. myocardium, lung, and brain). There is also evidence that XO-derived oxidants stimulate transcription of proinflammatory cytokines (IL-1β, TNF-α, and TGF-β1), in part, through activation of nuclear transcription regulatory factors. There also appears to be regulation of the vasoactive actions of ·NO by XO-generated oxidants to decrease rates of 02/·- generation, thus potentiating ·NO-mediated vasorelaxation. This regulation may be due to the reaction of ·NO with O2/·- to form ONOO-. Nitric oxide may also regulate O2/·- production post-transcriptionally by binding to the XO iron-sulfur moiety, sulfhydryl groups, or by reversible alteration of the flavin prosthetic site, thereby inhibiting activity. It is becoming apparent that tissue injury in MODS resulting from various pathologic states, including I/R, is the consequence not only excess production of reactive oxygen and nitrogen species (ROS and RNS) and their reaction with biologic target molecules, but also the effect of these oxidants in regulation of proinflammatory and anti-inflammatory mediators. The interplay of XO-generated oxidants and ·NO, has significant effects on cellular metabolism and organ function with their precise role in MODS requiring further elucidation. In summary, evidence was presented in this review that: (a) reactive species (ROS) are critical mediators of remote tissue injury; (b) ·NO and ·NO-derived oxidants contribute to the remote tissue damage; (c) XO, while a significant intracellular source of O2·-; is released into the circulation, binds, and concentrates on vessel walls to become a functionally critical source of oxidants even in tissues with low XO specific activity; and (d) that the balance between NO and O2/·- production determines whether the proinflammatory or anti-inflammatory properties are manifested.