Cancer cells undergo significant changes in metabolic patterns during carcinogenesis involving many aspects of sugar lipid amino acid and nucleic acid metabolism. It is the abnormal activation and reprogramming of these important metabolic pathways that endow cancer cells with unlimited proliferative potential and malignant biological features. Metabolic reprogramming in glioblastoma is also one of the distinctive features of tumorigenesis in which fatty acid metabolism also plays an important role in energy storage cell proliferation synthesis of important signaling molecules and chemoresistance. The treatment of glioblastoma still faces great challenges and resistance to the standard therapeutic agent temozolomide is one of the treatment difficulties. Chemoresistant glioblastoma cells exhibit more active levels of fatty acid metabolism compared to primary glioblastoma cells. Alterations in intra- and extracellular metabolites that accompany cancer-associated metabolic reprogramming have profound effects on gene expression cellular differentiation and tumor microenvironment. Chemoresistant glioblastoma cells have upregulated key enzymes and regulators of fatty acid metabolism with enhanced exogenous uptake de novo synthesis and oxidation of fatty acids providing major energy support for cells during therapeutic stress. Therefore targeting glioblastoma fatty acid metabolic pathways may be a new strategy to overcome chemoresistance in glioblastoma.