Cancer cells have enhanced metabolic needs due to their rapid proliferation. Moreover, throughout their progression from tumor precursors to metastases, cancer cells face challenging physiological conditions, including hypoxia, low nutrient availability, and exposure to therapeutic drugs. The ability of cancer cells to tailor their metabolic activities to support their energy demand and biosynthetic needs throughout disease progression is key for their survival. Here, we review the metabolic adaptations of cancer cells, from primary tumors to therapy resistant cancers, and the mechanisms underpinning their metabolic plasticity. We also discuss the metabolic coupling that can develop between tumors and the tumor microenvironment. Finally, we consider potential metabolic interventions that could be used in combination with standard therapeutic approaches to improve clinical outcome.