Acquisition by cancer cells of a plethora of resistance-conferring genetic alterations greatly limits the clinical utility of most anti- cancer drugs. Therefore, there is a need to improve the effective- ness of treatment before mutational-acquired resistance prevails. Relapse is driven by a small subpopulation of residual or ‘‘drug-tolerant’’ cells, which are traditionally called ‘‘minimal residual disease’’ (MRD), that remain viable upon drug exposure. Recent in vitro findings have indicated that the emergence of these per- sisters is unlikely due to mutational mechanisms. A non-mutually exclusive scenario proposes that the drug-tolerant phenotype is transiently acquired by a small pro- portion of cancer cells through non-mutational mechanisms. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant melanoma BRAF mutated cells, and we identified a subpopulation of melanoma cells is tolerant to targeted therapy via metabolic reprogramming. Cancer cells were known to reprogram their metabolic profiles geared toward glycolysis, despite sufficient oxygen available to support oxidative phosphorylation (OXPHOS), a phenomenon known as the Warburg effect. We found that melanoma MRD can switch their metabolic program from glycolysis towards mitochondrial OXPHOS alimented by fatty acid oxidation (FAO), thereby renders the melanoma MRD highly sensitive to FAO inhibition in vitro and in mouse tumor models. This MRD-directed metabolic reprogramming suggests a more clever treatment combination regimen to fight against cancer resistance.