Bacterial multidrug resistance (mdr) is an emerging threat to human health. Mdr can arise through one or more mechanisms. One, which is common to all domains, is the efflux of chemically and structurally dissimilar drugs by multidrug efflux transporters. How these multidrug efflux pumps recognise such different compounds is unknown, in great part due to the lack of high resolution structural data. Fortunately, many of the genes of these transporters are regulated by drug sensing transcription repressors or activators. Like the pumps they regulate, these transcription regulators are able to bind myriad structurally and chemically dissimilar drugs, nearly all of which are substrates for the efflux transporters that they regulate. In order to understand the structural basis of multidrug binding and recognition, we have determined the structures of several multidrug binding transcription regulators, including QacR and BmrR. QacR is a repressor that controls the transcription of the Staphylococcus aureus qacA gene, which encodes a multidrug efflux transporter that pumps out quaternary ammonium compounds (qacs). The substrates of the pump are monovalent and bivalent cationic aromatic/aliphatic disinfectants, antibiotics and antiseptics. When the QacA pump is overwhelmed, its substrates enter the cytoplasm whereby they bind to QacR and act as inducers, thereby allowing the derepression of the qacA gene and ultimately leading to more copies of the efflux pump. The structural mechanism of such “polyspecificity” that QacR utilises to recognise these chemically and structurally dissimilar inducers will be described. Briefly, the multidrug binding pocket can be described as a larger pocket composed of several “minipockets”. As might be anticipated, the multidrug binding pocket is lined with negatively charged residues, which play some role in neutralization of the cationic drug. However, that role is not as cardinal as might be expected. What is clear is the abundance of aromatic residues in the binding pocket and their role in drug binding will be described. Moreover, the multidrug binding mechanism of QacR will be compared and contrasted with that of BmrR, an activator of the bmr gene, which encodes a multidrug efflux transporter in Bacillus subtilis. Unlike QacR, BmrR appears to be more limited in the class of drugs that it binds, i.e., BmrR binds only aromatic/aliphatic monovalent cations. Regardless of the differences between QacR and BmrR and between QacR and other multi xenobiotic binding transcription factors, for which structural data are available, similar structural and chemical principles are employed by each of these multidrug binding proteins and will be described.