The molecular mechanisms by which tumor cells achieve an enhanced glycolytic flux and, presumably, a decreased oxidative phosphorylation are analyzed. As the O2 concentration in hypoxic regions of tumors seems not limiting for oxidative phosphorylation, the role of this mitochondrial pathway in the ATP supply is re-evaluated. Drugs that inhibit glycoysis and oxidative phosphorylation are analyzed for their specificity toward tumor cells and effect on proliferation. The energy metabolism mechanisms involved in the use of positron emission tomography are revised and updated. It is proposed that energy metabolism may be an alternative therapeutic target for both hypoxic (glycolytic) and oxidative tumors. © 2009 International Union of Biochemistry and Molecular Biology, Inc.