The critical role of mitochondria in cell fate decisions has been well documented over the years. These observations have highlighted the way mitochondrial physiology controls cell survival and growth in the normal settings, the critical role of mitochondrial outer membrane permeabilization and altered mitoenergetics in cell death execution, and most importantly the association of altered mitochondrial metabolism with pathological states, in particular cancer. Reprogramming of cell metabolism, an invariable finding in cancer cells, is tightly linked to mitoenergetics as is evidenced by up-regulation of nutrient uptake and a pro-oxidant tilt in the intracellular milieu. The latter has also been demonstrated in oncogene-induced carcinogenesis models, notably as a functional outcome of Bcl-2 overexpression. Interestingly, even in that model, mitochondria appear to be the target as well. Thus the association of metabolic re-circuiting and altered mitoenergetics with the process of transformation has resulted in a paradigm shift in the way cancer development and progression is viewed today, which has tremendous implications for the development of novel and strategic therapeutic modalities.