High levels of metal ions have the potential to cause cellular toxicity through a variety of mechanisms; therefore, cells have developed numerous systems that regulate their intracellular concentrations. The Cus resistance system aids in protection of Escherichia coli from high levels of Cu(I) and Ag(I) by actively transporting these metal ions to the extracellular environment. The Cus system forms a continuous complex, CusCBA, that spans the inner membrane, periplasm, and outer membrane of Gram-negative bacteria, together with a novel fourth component, the periplasmic metallochaperone, CusF. The metal-binding sites of CusA, CusB, and CusF are exquisitely tuned for Cu(I) and Ag(I), and thus effectively discriminate these ions for transport from other metals that may be required in the cell. Furthermore, direct transfer of metal from protein to protein within the Cus system during the transport process is likely to reduce the potential toxicity posed by the free metal ions. Here we review the wealth of structural, biochemical, and genetic information on the Cus system, which demonstrates the many intriguing aspects of function for metal-transporting efflux systems.