EmrE is a small (110 residues) SMR transporter from Escherichia coli that extrudes positively charged aromatic drugs in exchange for two protons, thus rendering bacteria resistant to a variety of toxic compounds. Due to its size, stability and retention of its function upon solubilization in detergent, EmrE provides a unique experimental paradigm for the biochemical and biophysical studies of membrane based ion-coupled transporters. In addition, EmrE has been in center stage in the past two years because it provides also a paradigm for the study of the evolution of membrane proteins. Controversy around this topic is still going on and some novel concepts are surfacing that may contribute to our understanding of evolution of topology of membrane proteins. Furthermore, based on the findings that the cell multidrug transporters interact functionally we introduce the concept of a cell Resistosome.