This review discusses the reprogramming of glucose metabolism in cancer cells, which is driven by oncogenic drivers and the undifferentiated nature of cancer cells. The reprogrammed glucose metabolism is essential for fulfilling anabolic demands, and the review explores the potential of exploiting this metabolic reprogramming for selective cancer therapy. It highlights the evolution of understanding in cancer metabolism, particularly the recognition of high cellular glucose metabolism as a hallmark of cancer. The review delves into the mechanisms of glucose metabolism reprogramming, including the regulation of glycolytic enzymes and the involvement of various pathways such as the pentose phosphate pathway (PPP), hexosamine pathway, and serine biosynthesis. It also discusses the regulation of these pathways by oncogenic proteins and tumor suppressors, and the role of hypoxia and the hypoxia-inducible factor 1 (HIF1) in accelerating glucose metabolism. The review further examines the selective targeting of cancer cells using glucose transporters and glycolytic enzymes, and the potential of combining glycolytic inhibitors with other therapies, such as immunotherapy, to enhance treatment efficacy. Finally, it addresses the challenges and future directions in exploiting reprogrammed glucose metabolism for cancer therapy.This review discusses the reprogramming of glucose metabolism in cancer cells, which is driven by oncogenic drivers and the undifferentiated nature of cancer cells. The reprogrammed glucose metabolism is essential for fulfilling anabolic demands, and the review explores the potential of exploiting this metabolic reprogramming for selective cancer therapy. It highlights the evolution of understanding in cancer metabolism, particularly the recognition of high cellular glucose metabolism as a hallmark of cancer. The review delves into the mechanisms of glucose metabolism reprogramming, including the regulation of glycolytic enzymes and the involvement of various pathways such as the pentose phosphate pathway (PPP), hexosamine pathway, and serine biosynthesis. It also discusses the regulation of these pathways by oncogenic proteins and tumor suppressors, and the role of hypoxia and the hypoxia-inducible factor 1 (HIF1) in accelerating glucose metabolism. The review further examines the selective targeting of cancer cells using glucose transporters and glycolytic enzymes, and the potential of combining glycolytic inhibitors with other therapies, such as immunotherapy, to enhance treatment efficacy. Finally, it addresses the challenges and future directions in exploiting reprogrammed glucose metabolism for cancer therapy.