Metabolic reprogramming is a hallmark of cancer, and recent advances have deepened our understanding of how tumors develop distinct metabolic phenotypes that differ from adjacent nonmalignant tissues. These phenotypes can be therapeutic vulnerabilities, but they also exhibit significant heterogeneity among human tumors. The metabolic properties and vulnerabilities of tumors evolve as they progress from premalignant lesions to locally invasive cancers and eventually to metastatic cancer. This evolution is driven by both intrinsic and extrinsic factors, including microenvironmental pressures and genetic changes. Early metabolic alterations in premalignant lesions may produce targetable liabilities, such as the accumulation of D-2-hydroxyglutarate in IDH1/2-mutant tumors. In primary invasive cancers, metabolic heterogeneity is influenced by molecular and microenvironmental factors, leading to diverse metabolic vulnerabilities. Metastatic cancer imposes distinct metabolic requirements, such as the ability to resist oxidative stress and increased reliance on oxidative phosphorylation (OXPHOS). Targeting metabolic liabilities, such as OXPHOS, may be effective in therapy-resistant states, but challenges remain in identifying the most suitable patients for these treatments. Advanced techniques in metabolic analysis, including metabolomics, metabolic isotope tracers, and metabolic imaging, are crucial for assessing tumor metabolism and developing more precise therapeutic strategies.Metabolic reprogramming is a hallmark of cancer, and recent advances have deepened our understanding of how tumors develop distinct metabolic phenotypes that differ from adjacent nonmalignant tissues. These phenotypes can be therapeutic vulnerabilities, but they also exhibit significant heterogeneity among human tumors. The metabolic properties and vulnerabilities of tumors evolve as they progress from premalignant lesions to locally invasive cancers and eventually to metastatic cancer. This evolution is driven by both intrinsic and extrinsic factors, including microenvironmental pressures and genetic changes. Early metabolic alterations in premalignant lesions may produce targetable liabilities, such as the accumulation of D-2-hydroxyglutarate in IDH1/2-mutant tumors. In primary invasive cancers, metabolic heterogeneity is influenced by molecular and microenvironmental factors, leading to diverse metabolic vulnerabilities. Metastatic cancer imposes distinct metabolic requirements, such as the ability to resist oxidative stress and increased reliance on oxidative phosphorylation (OXPHOS). Targeting metabolic liabilities, such as OXPHOS, may be effective in therapy-resistant states, but challenges remain in identifying the most suitable patients for these treatments. Advanced techniques in metabolic analysis, including metabolomics, metabolic isotope tracers, and metabolic imaging, are crucial for assessing tumor metabolism and developing more precise therapeutic strategies.