Organ damage can occur quickly when blood flow is compromised. Lactic acidosis has long been associated with such ischemia, and many physicians assume that organ damage is caused by this acidosis. However, reviewing the literature related to hypoxia and ischemia reveals little data to support the concept of acidosis as damaging to tissue. In contrast, recent studies indicate that the acidosis is actually protective, even during reperfusion when cellular damage may occur. Reperfusion is accompanied by generation of free radicals and other reactive species that can damage proteins, membranes, and nucleic acids, supporting an emerging view that implicates these reactive species in the actual tissue damage. The critical targets of the damaging species are not known, but reaction with key enzymes and structural proteins could certainly disrupt organ function. Cellular proteins are oxidatively modified during reperfusion, in part by metal-catalyzed oxidation in which cellular iron plays a key role. Metal-cataly...