In view of the current limitations of cancer chemotherapy, there has been resurgent interest in re-visiting glycolysis to determine whether tumors could be killed by energy deprivation rather than solely by strategies to inhibit proliferation. Cancer cells exhibit a uniquely high rate of glucose utilization, converting it into lactate whose export subsequently creates an acidic extracellular environment that is thought to promote invasion and metastasis, in preference to its complete oxidation even in the presence of adequate oxygen supply. Reductive analysis of each step of glycolysis shows that, of the three rate limiting enzymes of the pathway, isoforms of phosphofructokinase may afford the greatest opportunity as targets to deprive cancer cells from essential energy and substrates for macromolecular synthesis for proliferation while allowing normal cells to survive. Strategies discussed include restricting the substrate for this enzyme. While prospects for monotherapy with glycolytic inhibitors are poor, combination therapy may be productive.