Introduction Pseudomonas aeruginosa is a gram-negative bacterium that can survive in different environments, including soil, plants, and animals. Moreover, it is the most opportunistic human pathogen, particularly in immunocompromised patients, and has been recognized as one of the five main pathogens in nosocomial infections. 1 Pseudomonas diseases are mainly seen in urinary tract infections (UTIs), burn wounds, and pulmonary infections such as cystic fibrosis (CF). Mortality rates in P. aeruginosa infections are up to 50% and 70% in patients with bacteremia and nosocomial pneumonia, respectively. 2 P. aeruginosa infections are diverse, because they have a multiplicity of resistance mechanisms and have developed different metabolic and nutritional pathways. 3 Of the resistance mechanisms to be noted is the formation of biofilms, which provide better protection against different antibiotics and body defense systems. 3 Additionally, low outer cell membrane permeability causes intrinsic resistance to antibiotics and increases the number of multi-drug resistance (MDR) strains in P. aeruginosa (resistance ≥3 antibiotic classes). 4-7 Moreover, the high expression of efflux pumps can rapidly expand antibiotic resistance as well. 8 This review discusses types of efflux pumps, the efflux pumps role in pathogenicity, the importance of efflux pump inhibitors (EPIs), diagnostic methods for their detection, and compounds derived from natural sources that reduce infections caused by MDR P. aeruginosa. Efflux Pumps and Their Importance in Antibiotic Resistance Since the discovery of bacterial efflux pumps in the 1980s, many of them have been characterized. 9 Efflux pumps are membrane proteins and participate in the extrusion of antibiotics and chemicals such as organic solvents, dyes, detergents, intermediate molecules in cellular communications, metabolic products, and biocides in prokaryote and eukaryote cells. 10 Substrates of note of the efflux pumps are oxazolidinones