Mitochondria are at the crossroads of several crucial cellular activities including: adenosine triphosphate (ATP) generation via oxidative phosphorylation; the biosynthesis of heme, pyrimidines and steroids; calcium and iron homeostasis and programmed cell death (apoptosis). Mitochondria also produce considerable quantities of superoxide and hydrogen peroxide (H2O2) that in conjunction with its large iron stores can lead to a witch's brew of reactive intermediates capable of damaging macromolecules. Mitochondrial DNA (mtDNA) represents a critical target for such oxidative damage. Once damaged, mtDNA can amplify oxidative stress by decreased expression of critical proteins important for electron transport leading to a vicious cycle of reactive oxygen species (ROS) and organellar dysregulation that eventually trigger apoptosis. Oxidative stress is associated with many human disorders including: cancer, cardiovascular disease, diabetes mellitus, liver disease and neurodegenerative disease. This article reviews the evidence that oxidative damage to mtDNA can culminate in cell death and thus represents an important target for therapeutic intervention in a number of human diseases.