The article by Hiroshi Nikaido discusses the mechanisms of multidrug resistance in bacteria, which have emerged due to the extensive use of antibiotics in human therapy and agriculture. Multidrug resistance can be generated through two primary mechanisms: the accumulation of multiple resistance genes on resistance (R) plasmids or the increased expression of genes coding for multidrug efflux pumps. The review covers the molecular mechanisms involved in both types of resistance, including mutational alterations of target proteins, enzymatic inactivation of drugs, and the acquisition of genes for less susceptible target proteins from other species. It also explores the assembly, maintenance, and transfer of resistance genes, as well as the role of multidrug efflux pumps in drug resistance. The article highlights the importance of RND pumps, particularly in gram-negative bacteria, and provides insights into their structure, function, and regulation. Additionally, it discusses the development of inhibitors for RND multidrug efflux pumps and the "natural" substrates for these pumps.The article by Hiroshi Nikaido discusses the mechanisms of multidrug resistance in bacteria, which have emerged due to the extensive use of antibiotics in human therapy and agriculture. Multidrug resistance can be generated through two primary mechanisms: the accumulation of multiple resistance genes on resistance (R) plasmids or the increased expression of genes coding for multidrug efflux pumps. The review covers the molecular mechanisms involved in both types of resistance, including mutational alterations of target proteins, enzymatic inactivation of drugs, and the acquisition of genes for less susceptible target proteins from other species. It also explores the assembly, maintenance, and transfer of resistance genes, as well as the role of multidrug efflux pumps in drug resistance. The article highlights the importance of RND pumps, particularly in gram-negative bacteria, and provides insights into their structure, function, and regulation. Additionally, it discusses the development of inhibitors for RND multidrug efflux pumps and the "natural" substrates for these pumps.