Multidrug transporters have long puzzled researchers because of their ability to extrude multiple structurally dissimilar toxic chemotherapeutic agents. They appear to be essentially ubiquitous with many microorganisms possessing large arsenals of predicted multidrug efflux transporters. Recent reports on the structures of multidrug efflux transporters and their cognate regulators have suggested that the basis of multidrug recognition is the presence of large flexible hydrophobic cavities capable of accommodating different compounds that are bound via hydrogen bonding and/or electrostatic interactions. This structural data provides the context for understanding other questions about the evolution of multidrug transporters and their natural physiological roles.