ABC (ATP-binding cassette) transporters are ubiquitous integral membrane proteins catalyzing the active export or import of structurally and functionally unrelated compounds. In humans, these proteins are clinically and economically important, as their dysfunction is responsible for a number of diseases. In the case of multidrug resistance (MDR) ABC exporters, they particularly confer resistance to a broad spectrum of toxic compounds, placing them in the focus of clinical research. However, ABC-mediated drug resistance is not only restricted to humans. In yeast for example, MDR is called pleiotropic drug resistance (PDR). Important and well-studied members of the PDR subfamily of ABC transporters are Pdr5 from Saccharomyces cerevisiae and its homolog Cdr1 from Candida albicans. Mutational studies of these two transporters provided many insights into the complexity and conceivable mechanism of the interdomain cross-talk that transmits the energy gained from ATP hydrolysis to the substrate translocation process across the membrane. In this review, we summarize and discuss our current knowledge of the interdomain cross-talk as well as new results obtained for asymmetric ABC transporters and derive possible structural and functional implications for Pdr5.