Acquired multidrug resistance (MDR) in pathogenic microbials is a world-wide threat to human health. Several MarR–like proteins regulate the expression of efflux pumps, which are multiprotein self-assembly complexes actively extruding chemical compounds with high toxicity to the host organism. Since incapacitating the repressor protein leads to continuously high production of the efflux proteins and thus increased survival for the bacteria, there is a high mutational pressure for acquired MDR. MexR is a key member of the MarR family, and is also mutated in MDR. Analyzing the structure–function relationships of MarR family proteins, both in their native and mutated forms, is fundamental to learn how to overcome innate and acquired MDR in future drug development.