Introduction: Worrying levels of bacterial resistance have been reported worldwide involving the failure of many available antibiotic treatments. Multidrug resistance (MDR) in Gram-negative bacteria is often ascribed to the presence of multiple and different resistance mechanisms in the same strain. RND efflux pumps play a major role and are an attractive target to discover new antibacterial drugs. Areas covered: This review discusses the prevalence of efflux pumps, their overexpression in clinical scenarios, their polyselectivity, their effect on the intracellular concentrations of various antibiotics associated with the alteration of the membrane permeability and their involvement in pathogenicity are discussed. Expert opinion: Efflux pumps are new targets for the development of adjuvant in antibiotic treatments by of efflux pump inhibition. They may allow us to rejuvenate old antibiotics acting on their concen-tration inside the bacteria and thus potentiating their activity while blocking the release of virulence factors. It is a pharmacodynamic challenge to finalize new combined therapy. KEYWORDSEfflux pump; Gram-negative bacteria; antibiotic; multidrug resistance; inhibitor Article highlights• Efflux pumps play a major role in multidrug resistance in Gram-negative bacteria • The pharmacodynamic role of RND efflux pumps in antibiotic resis-tance opens up new perspectives to alternative therapeutics • Targeting efflux pumps consists in solving the problems of polyse-lectivity, drug accumulation, membrane permeability and pathogeni-city related to bacterial resistance mechanisms • How to validate efflux pumps as target for new combined therapy?• Efflux pump inhibitor could be used as adjuvant in antibiotic treatments