Metabolic pathways play a significant role in cancer, and their disturbances have been shown to result in therapy resistance. Upregulation of glycolysis, involving key players like GLUT1, HK2, and LDH, promotes an enhanced metabolism of glucose, as well as anabolic processes within resistant cancer cells. Additionally, the resistance of cells involves how they rewire mitochondrial metabolism and engage in dynamic cycles of fission and fusion in response to therapeutic stress. Important contributions come from mitochondrial function, particularly the components of oxidative phosphorylation (OXPHOS). Glutamine dependency and serine-glycine metabolic modification were some of the mechanisms put in place that facilitate the proliferation of tumor cells even in stressful conditions. Lipid metabolism, particularly the role of fatty acid oxidation in meeting energy demands during treatment, is crucial. Additionally, lipogenesis serves as an adaptive process to counteract stress induced by treatment. The processes that contribute to metabolic reprogramming involve hypoxia-induced adaptation through hypoxia-inducible factors, oncogenic signaling networks like PI3K/AKT/mTOR, and epigenetic regulation of metabolic gene expression. In this chapter, the possibility of using metabolic biomarkers in predicting resistance to therapy is also covered, along with their application in clinical use for tailoring treatment to individual needs. It primarily emphasizes therapeutic targeting of metabolic vulnerabilities, such as glycolysis inhibitors, OXPHOS, inhibitors of amino acid metabolism, and lipid metabolism inhibitors. This chapter also covers the new and emerging combination therapies combining metabolic inhibitors with standard therapy and considers dietary intervention as an adjunct strategy. This chapter underlines future precision oncology through the integration of multi-omics technologies and artificial intelligence to identify metabolic resistance in cancer therapy.