Mammalian cells are continuously subject to insult from reactive species. Most of the pathogenic mechanisms that have been considered to date reflect overproduction of reactive oxygen species (ROS) or a peculiar failure in intracellular defenses against ROS. We have attempted to consider briefly the most important mechanisms of ROS production, defense, and reactive species-induced cell damage and approaches to therapy, focusing on the example of diabetes mellitus. An improved understanding of these mechanisms should facilitate development of antioxidant intervention strategies leading to reduction in diseases associated with oxidative stress.