Tissue iron overload causes clinical syndromes that involve the heart, liver, and pancreas. While tissue iron uptake occurs by both transferrin-dependent and independent processes, tissue uptake in the iron overload syndromes occurs predominantly via transferrin-independent mechanisms. Increased redox-active iron present in hemeproteins and the cytosolic iron pool can catalyze oxidative damage to lipids, proteins, and nucleic acids, either by oxyradical dependent or independent mechanisms. Iron-catalyzed injury results in damage to cell constituents, including mitochondria, lysosomes, and the sarcolemmal membrane. These mechanisms of iron-mediated damage are involved in the pathogenesis of organ dysfunction in primary hemochromatosis, transfusion-related iron overload, ischemia-reperfusion injury, and cardiac anthracycline toxicity.