This review focuses on the physiology of mitochondria as well as on the role of mitochondrial changes in cancer and in the immune system. After discussing the origin, structure, function and physiology of mitochondria, we focus on mitochondrial damage induced by antiviral and other drugs, reactive oxygen intermediates, physical tests like heat shock and ionizing radiation, hypoxia and hyperoxia. While discussing the effects of these noxious stimuli on mitochondria, we introduce terms such as “mitotoxicity” and “mitotoxins”. Further parts of the review focus on the role of mitochondria in programmed cell death, and mitochondrial dysfunction observed in cancer. A significant portion of the review discusses the role of mitochondrial changes during the aging of the immune system, age-related changes of mitochondrial physiology, and mitochondrial proteins as auto-antigens. Using primary biliary cirrhosis as an example, we illustrate that the autoimmune condition is perpetuated by a pathologic immune response directed towards mitochondrial antigens. Finally we raise several questions, which we believe, need to be answered in order to improve the therapy of cancer autoimmunity and genetic diseases involving mitochondria.