For decades, tumor cells have been considered defective in mitochondrial respiration due to their dominant glycolytic metabolism. However, a growing body of evidence is now challenging this assumption, and also implying that tumors are metabolically less homogeneous than previously supposed. A small subpopulation of slow-cycling cells endowed with tumorigenic potential and multidrug resistance has been isolated from different tumors. Deep metabolic characterization of these tumorigenic cells revealed their dependency on mitochondrial respiration versus glycolysis, suggesting the existence of a common metabolic program active in slow-cycling cells across different tumors. These findings change our understanding of tumor metabolism and also highlight new vulnerabilities that can be exploited to eradicate cancer cells responsible for tumor relapse.