The clinical and economic impacts of bacterial resistance are substantial. The development of bacterial resistance during a course of therapy often leads to clinical failure, prolonged hospitalization, increased morbidity, mortality, and increased health care costs. Resistance has been reported to occur most frequently with aminoglycosides, quinolones, and beta-lactam antimicrobials, and often occurs during the course of treatment of gram-negative bacillary infection. Resistance is most commonly due to enzymatic inactivation, permeability changes, or receptor mutation. Strategies for the prevention of resistance include appropriate infection-control practices, judicious use of antimicrobials, enhancement of host defenses, and the use of antimicrobial combinations. Despite success in vitro and in experimental animal models of infection, clinical trials in humans of antimicrobial combinations for the prevention of resistance have yielded mixed results. Use of the most potent agents available, preferably in bactericidal synergistic combinations, may be effective in preventing in vivo emergence of bacterial resistance.