Antimicrobial stewardship is a key component of a multifaceted approach to preventing emergence of antimicrobial resistance. Good antimicrobial stewardship involves selecting an appropriate drug and optimizing its dose and duration to cure an infection while minimizing toxicity and conditions for selection of resistant bacterial strains. Studies conducted over the years indicate that antibiotic use is unnecessary or inappropriate in as many as 50% of cases in the United States, and this creates unnecessary pressure for the selection of resistant species. Because the pharmaceutical industry pipeline for new antibiotics has been curtailed in recent years, and it may be ≥10 years before important new antibiotics to treat certain resistant bacteria find their way to market, a premium has been set on maintaining the effectiveness of currently available agents. Several strategies, including prescriber education, formulary restriction, prior approval, streamlining, antibiotic cycling, and computer-assisted programs have been proposed to improve antibiotic use. Although rigorous clinical data in support of these strategies are lacking, the most effective means of improving antimicrobial stewardship will most likely involve a comprehensive program that incorporates multiple strategies and collaboration among various specialties within a given healthcare institution. Computer-assisted software programs may be especially useful in implementing these comprehensive programs. The antimicrobial stewardship program at the Hospital of the University of Pennsylvania, which has been shown to improve appropriateness of antibiotic use and cure rates, decrease failure rates, and reduce healthcare-related costs, is used as an example in support of this multifaceted, multidisciplinary approach. At this time, data from well-controlled studies examining the effect of antibacterial stewardship on emergence of resistance are limited, but available data suggest that good antibiotic stewardship reduces rates of Clostridium difficile–associated diarrhea, resistant gram-negative bacilli, and vancomycin-resistant enterococci.