Multidrug efflux transporters, found in all living cells and protecting them from multiple structurally dissimilar hydrophobic toxins, have fascinated researchers for decades and presented a number of puzzling questions. These transporters demonstrate a remarkably broad substrate specificity, which seemingly contradicts established dogmas of biochemistry. Although sharing highly unusual properties, in some unexplained way, they have arisen multiple times in the evolution of several families of membrane proteins. Furthermore, the number of multidrug transporters encoded in each genome is so large that their role in cellular physiology has remained un-certain. Recent advances in the structural analysis of a number of soluble multidrug-recognizing proteins show that these proteins possess large hydrophobic binding sites and bind their substrates through a combination of a hydrophobic effect and electrostatic attraction, rather than by establishing a precise network of hydrogen bonds and other specific interactions characteristic of traditionally studied enzymes and receptors. Low-resolution structural studies of multidrug transporters suggest that they possess similar large binding sites and may use similar simple principles of substrate recognition. This would explain not only their broad substrate specificity, but also their unusual evolutionary relationships and the apparent multiplicity in genomes of organisms of all evolutionary kingdoms. Although further structural studies will be needed to prove this hypothesis, it is already clear that the explanation of the puzzling phenomenon of multidrug efflux may not necessarily require any substantially new biochemical or biological principles.