Superoxide dismutase (SOD) has now been known for 35 years. While the superoxide radical and SOD have been implicated in many disease states including inflammatory diseases, diseases of ischemia and reperfusion, neurodegenerative diseases, and cancer, as well as more subtle roles in cell signaling and perhaps in immune function, SOD is not yet in widespread usage in human clinical medicine. One obstacle has been that none of the three human SODs possesses attractive pharmacological properties to make it a clinically useful therapeutic agent. These problems may be overcome either by the design of SOD-mimetic drugs or by genetically re-engineering the human SOD genes to produce SODs with more desirable and controllable properties for human clinical usage. A second obstacle has been the fact that a delicate balance is involved between superoxide and SOD. Produced in proper amount, superoxide is a normal and useful metabolite, serving important roles as a signaling molecule in processes such as cell division, and even serving to act as a terminator of lipid peroxidation. When flagrantly overproduced, however, the radical can initiate lipid peroxidation, protein oxidation, and DNA damage, leading to cell dysfunction and death by apoptosis or necrosis. It is these paradoxical properties that complicate the precise restoration of optimal balance between superoxide and SOD when that balance has been upset by injury, disease, or aging.