Mitochondria have been an area of scientific study for more than 100 years (Table 1). It was in the early twentieth century that Otto Warburg first described differences in the mitochondria of tumor vs. normal cells. He observed that tumor cells had an increased rate of aerobic glycolysis compared with normal cells. He hypothesized that this increase was due to the impairment in the respiratory capacity of tumor cells (Warburg 1930, 1956). This was the first of several notable differences observed between the mitochondria of normal and transformed cells that were subsequently discovered (reviewed in Weinhouse 1955; Pedersen 1978; Carafoli 1980; Modica-Napolitano and Singh 2002, 2004; Modica-Napolitano et al. 2007). The physical structure, composition, and function of mitochondria differ greatly from that of tumor and normal cells. For example, the mitochondria of many rapidly growing tumors are fewer in number, smaller, and have fewer cristae than do mitochondria from slowly growing tumors, which tend to have characteristics more closely resembling those of normal cells. Polypeptide profiles, as well as lipid composition of the inner mitochondrial membrane of tumor cells, differ from those of normal cells. Additional differences between the mitochondria of normal vs. transformed cells also have been described with regard to the preference for substrates, mitochondrial membrane potential, rates of electron transfer, anion transport, protein synthesis, organelle turnover, and reactive oxygen species (ROS) production. © 2009 Springer New York.