Gram-negative bacteria remain clinically important pathogens in both hospital and community settings. Recent research indicates that efflux pumps play a prominent role in the multidrug resistance of Pseudomonas aeruginosa and many other gram-negative bacteria. Four multidrug efflux pump systems have been well characterized in P. aeruginosa: MexA-MexB-OprM, MexC-MexD-OprJ, MexE-MexF-OprN, and MexX-MexY-OprM. These efflux pumps have different substrate specificities, and their production and activity can be increased by many factors commonly present in infections (e.g., high inocula of bacteria, low pH, and stationary-phase growth). Moreover, fluoroquinolone antibiotics can commonly select mutants that constitutively overproduce Mex-Opr efflux pump systems. Based on most recent studies, the prevalence of efflux pump overproduction in clinical strains of P. aeruginosa may range from 14-75%. The best treatment for infections caused by bacteria that overproduce efflux pumps is unknown, but pharmacodynamic optimization of antibiotics and the use of antibiotic combinations that are substrates for different pump systems may represent reasonable strategies until more data are available.