The role of PI-3-K in the regulation of mitochondrial functions is becoming a field that draws attentions from cancer as well as metabolic diseases. In this review, we focus on the action of the major downstream target of PI-3-K, the serine/threonine kinase AKT, a proto-oncoprotein. We reviewed the functions of AKT in the mitochondrial intrinsic apoptosis pathway. We analyzed how AKT regulates the different factors in the Bcl-2 family of anti- and pro-apoptotic factors either directly or indirectly. We further reviewed the role of AKT in regulating mitochondrial coupled glycolysis through hexokinase II and VDAC. This review is focused on the function of PI-3-K and AKT at the mitochondrial. These interactions between the mitogenic PI-3-K/AKT and the mitochondrial function may provide clues on how tumors overcome the ongoing need for nutrient supply. Such characterizations can provide new targets for drug discoveries targeted at blocking tumor progression.