Multidrug-resistant strains of Salmonella are now encountered frequently, and the rates of multidrug resistance have increased considerably in recent years. Here, we report that the two-component regulatory system BaeSR increases multidrug and metal resistance in Salmonella through the induction of drug efflux systems. Screening of random fragments of genomic DNA for the ability to increase beta-lactam resistance in Salmonella enterica led to the isolation of a plasmid containing baeR, which codes for the response regulator of BaeSR. When overexpressed, baeR significantly increased the resistance of the delta acrB strain to oxacillin, cloxacillin, and nafcillin. baeR overexpression conferred resistance to novobiocin and deoxycholate, as well as to beta-lactams in Salmonella. The increase in drug resistance caused by baeR overexpression was completely suppressed by deletion of the multifunctional outer membrane channel gene tolC. TolC interacts with different drug efflux systems. Among the nine drug efflux systems in Salmonella, quantitative real-time PCR analysis showed that BaeR induced the expression of acrD and mdtABC. Double deletion of these two genes completely suppressed BaeR-mediated multidrug resistance, whereas single deletion of either gene did not. The promoter regions of acrD and mdtABC harbor binding sites for the response regulator BaeR, which activates acrD and mdtABC transcription in response to indole, copper, and zinc. In addition to their role in multidrug resistance, we found that BaeSR, AcrD, and MdtABC contribute to copper and zinc resistance in Salmonella. Our results indicate that the BaeSR system increases multidrug and metal resistance in Salmonella by inducing the AcrD and MdtABC drug efflux systems. We found a previously uncharacterized physiological role for the AcrD and MdtABC multidrug efflux systems in metal resistance.