Mitochondria have been increasingly implicated in being a crucial subcellular target and amplifying oxidative injury induced by many drugs. Among the major cytoprotective antioxidants is the mitochondrial matrix protein, superoxide dismutase-2 (SOD2). Genetic modification of the expression of SOD2 by transgenic techniques or gene silencing has generated a number of distinct animal models with SOD2 deficiency including the heterozygous Sod2(+/-) knockout mouse model. These mice display a discreet underlying mitochondrial stress but are otherwise phenotypically normal and thus model a variety of clinically silent mitochondrial abnormalities. The model has found application in oxidative stress and age-related research, but it is only recently that it has been successfully used to study mechanisms of idiosyncratic drug-induced liver injury.