Abstract: The proliferation of tumor cells is an extremely energy-consuming process. However, different from normal cells, tumor cells generate energy via glycolysis even under aerobic conditions, which is one of the ten hallmarks of tumor cells. The switch of energy metabolism results in a series of physiological changes in tumor cells, including rapid generation of ATP and abundent biomass for cell proliferation, which form the basis of tumor cells to successfully adapt to their extreme microenvironment (e.g. lack of oxygen). In this review, we will introduce recent progress in studying somatic mutations on the energy metabolism related genes in tumors, with special focus on the potential factors involving in the “switch” and to decipher the genetic adaptive footprint of the “switch” from the angle of molecular evolution.