Multidrug transporters play a crucial role in causing drug resistance in infectious microorganisms and tumors. They are integral membrane proteins that exhibit an exceptionally broad specificity for unrelated molecules including antibiotics and anticancer agents. By mediating export of toxic pharmaceuticals from the cell’s interior, multidrug transporters reduce the concentration of these agents in the cell to a level where toxicity is lost. In spite of intense efforts, it is still not clear exactly how multidrug transporters work. In this chapter, we discuss some of the recent advances for multidrug transporters in two important families, the major facilitator superfamily (MFS) and multidrug and toxic compound extrusion (MATE) family.