Increasingly, perturbations in cellular iron and ferritin are emerging as an important element in the pathogenesis of disease. These changes in ferritin are important not only in the classic diseases of iron acquisition, transport, and storage, such as primary hemochromatosis, but also in diseases characterized by inflammation, infection, injury, and repair. Among these are some of the most common diseases that afflict mankind: neurodegenerative diseases such as Parkinson disease1 and Alzheimer disease, 2 vascular diseases such as cardiac and neuronal ischemia-reperfusion injury, 3, 4 atherosclerosis itself, 5 pulmonary inflammatory states, 6 rheumatoid arthritis, 7, 8 and a variety of premalignant conditions and frank cancers. 9 We are just beginning to learn the mechanisms and implications of alterations in ferritin and iron homeostasis from these natural “experiments.” However, what is increasingly apparent is that ferritin appears to be a key molecule that limits the extent, character, and location of the pro-oxidant stress that typifies inflammatory diseases, cancer, and conditions of altered oxygenation. The link between alteration in ferritin regulation and these diseases is forged through a diverse set of cellular stress pathways that alter ferritin subunit composition and/or content within cells. The 2 broad themes developed in this review are that understanding the signals and pathways that regulate ferritin may lead to insights into the pathophysiology of these diseases, and that attention to how ferritin responds to stress will in turn teach us more about the normal functions of this complex protein.