The main purpose of this review is to update and analyze the effect of several antineoplastic drugs (adriamycin, apoptodilin, casiopeinas, cisplatin, clotrimazole, cyclophosphamide, ditercalinium, NSAIDs, tamoxifen, taxol, 6-mercaptopurine, and alpha-tocopheryl succinate) and energy metabolism inhibitors (2-DOG, gossypol, delocalized lipophilic cations, and uncouplers) on tumor development and progression. The possibility that these antineoplastic drugs currently used in in vitro cancer models, in chemo-therapy, or under study in phase I to III clinical trials induce tumor cellular death by altering also metabolite concentration (i.e., ATP), enzyme activities, and/or energy metabolism fluxes is assessed. It is proposed that the use of energy metabolic therapy, as an alternative or complementary strategy, might be a promising novel approach in the treatment of cancer.