Major metabolic changes that affect the balance between respiration and glycolysis occur during carcinogenesis. It is therefore not surprising that it has long been suggested that abnormal activity of the mitochondrial electron transfer chain could play a role in the underlying pathophysiologic process. However, it has only recently been demonstrated that the specific impairment of one component of the electron transfer chain, namely complex II, can indeed be the primary event triggering carcinogenesis. Unexpectedly, rather than superoxide overproduction, the organic acid imbalance resulting from the complex II blockade appears to be instrumental in the early step of tumorigenesis. Nevertheless, because an abnormal handling of oxygen is frequently suspected of being associated with electron transfer dysfunction, a renewed interest is observed for the putative instability of the mitochondrial genome often reported in tumor tissues. In this chapter, we review and discuss the evidence advocated for the implication of the electron transfer chain in carcinogenesis.