The metabolic reprogramming of cell is a well-established clinical hallmark of cancer and accordingly has attracted significant attention from researchers in the field of drug discovery. The dependency of cancer cells toward altered “cancer metabolism” (CM) encouraged scientists to work to better understand their metabolic alteration and tumor microenvironment. In fact, the cellular energetics of cancer cells is significantly different from normal cells due to the high demand of energy and metabolites that are required for cancer cell growth and proliferation. A combination of identification of metabolic processes and detailed study of how oncogenic signaling pathways can modulate the metabolic processes might be useful to achieve the selective killing of cancer cells. Recently, several studies have confirmed that cancer metabolism plays a fundamental role in cancer progression and metastasis. Carbohydrate metabolism, particularly glucose metabolism in tumor cells, has received significant attention because rapidly growing cancer cells preferentially rely on the enhanced rate of tumor glycolytic process uncoupled with oxidative phosphorylation. Small molecules targeting tumor glycolysis hold promise for drug discovery and drug development in cancer therapeutics. In addition, it offers the development of new treatment options by synergizing potential glycolytic inhibitors with existing drugs. Therefore, this article includes recent updates on tumor glycolysis and small molecules that counteract tumor glycolysis.