The article reviews the role of bacterial efflux pump inhibitors in addressing antibiotic resistance. Bacterial resistance is a growing global concern, leading to increased mortality and economic losses. Efflux pumps are a significant factor in the development of resistance to various antibiotics, and their overexpression increases bacterial resistance. Efflux pump inhibitors, small molecules that restore the effectiveness of antibiotics, have emerged as potential solutions. The article discusses the mechanisms of bacterial resistance, including altered cell permeability, molecular target changes, antibiotic inactivation, and efflux pump expression. It highlights the importance of understanding efflux pumps, particularly in Gram-positive and Gram-negative bacteria, and their role in drug resistance. The article provides a detailed overview of efflux pump inhibitors for common clinical pathogens such as *Staphylococcus aureus*, *Klebsiella pneumoniae*, *Pseudomonas aeruginosa*, *Escherichia coli*, and *Campylobacter jejuni*. These inhibitors, derived from natural and synthetic sources, have shown promise in increasing the susceptibility of bacteria to antibiotics. Examples include capsaicin, piperine, dihydroquinazoline, β-naphthylamide, berberine, quercetin, epigallocatechin-3-gallate, glycyrrhizin, and phenolic compounds. The article also discusses the screening methods and key technologies used to identify these inhibitors, including virtual screening and physical experiments. The article further explores the multifaceted benefits of efflux pump inhibitors, including their ability to inhibit biofilm formation, reduce bacterial virulence, decrease the formation of bacterial persister cells, limit the acquisition of bacterial resistance, and improve mismatch repair. These inhibitors can enhance the effectiveness of antibiotics, reduce the emergence of resistant strains, and improve the overall success of antimicrobial therapy. In conclusion, the application of efflux pump inhibitors holds significant potential in addressing and reducing bacterial resistance, making them a valuable tool in the fight against antibiotic-resistant infections.The article reviews the role of bacterial efflux pump inhibitors in addressing antibiotic resistance. Bacterial resistance is a growing global concern, leading to increased mortality and economic losses. Efflux pumps are a significant factor in the development of resistance to various antibiotics, and their overexpression increases bacterial resistance. Efflux pump inhibitors, small molecules that restore the effectiveness of antibiotics, have emerged as potential solutions. The article discusses the mechanisms of bacterial resistance, including altered cell permeability, molecular target changes, antibiotic inactivation, and efflux pump expression. It highlights the importance of understanding efflux pumps, particularly in Gram-positive and Gram-negative bacteria, and their role in drug resistance. The article provides a detailed overview of efflux pump inhibitors for common clinical pathogens such as *Staphylococcus aureus*, *Klebsiella pneumoniae*, *Pseudomonas aeruginosa*, *Escherichia coli*, and *Campylobacter jejuni*. These inhibitors, derived from natural and synthetic sources, have shown promise in increasing the susceptibility of bacteria to antibiotics. Examples include capsaicin, piperine, dihydroquinazoline, β-naphthylamide, berberine, quercetin, epigallocatechin-3-gallate, glycyrrhizin, and phenolic compounds. The article also discusses the screening methods and key technologies used to identify these inhibitors, including virtual screening and physical experiments. The article further explores the multifaceted benefits of efflux pump inhibitors, including their ability to inhibit biofilm formation, reduce bacterial virulence, decrease the formation of bacterial persister cells, limit the acquisition of bacterial resistance, and improve mismatch repair. These inhibitors can enhance the effectiveness of antibiotics, reduce the emergence of resistant strains, and improve the overall success of antimicrobial therapy. In conclusion, the application of efflux pump inhibitors holds significant potential in addressing and reducing bacterial resistance, making them a valuable tool in the fight against antibiotic-resistant infections.