Here, we identified a long-chain acyl-CoA-responsive transcriptional repressor, FdmR, as the key regulator of mycobacterial fatty acid catabolism. We employed RNA-Seq to identify the differentially expressed genes between wild-type M.marinum and FdmR mutant. Among the most highly differentially expressed genes, we observed a considerable up-regulation of the genes (fadA2, fadE12_3, fadE23-fadE24, echA8_7, echA10_1, desA3, acrA1, and fabG4-htdX) involved in fatty acid metabolism in the FdmR mutant. We then demonstrated that FdmR acts as a valve to direct the fatty acid flux from beta-oxidation towards lipid biosynthesis, thereby avoiding the overactive catabolism and accumulation of biologically toxic intermediates. This regulatory mechanism enables a high rate of cell growth with modest consumption of fatty acid substrates.