The historical development of antibiotic resistance, mechanisms of resistance, classification schemes for beta-lactamases, the clinical relevance of resistance, and approaches to overcoming resistance are reviewed. The promise of eradication of infectious diseases has not been fulfilled, in great part owing to the emergence of antibiotic-resistant organisms. Although genes for bacterial resistance may have existed before the clinical use of antibiotics, selection of new resistant strains is driven by the widespread use of antimicrobials in humans and animals. The most commonly prescribed antimicrobials in the United States are the beta-lactam antibiotics, and the most common mechanism of bacterial resistance to these agents is inactivation by beta-lactamase. The clinical and economic consequences of therapeutic failure and relapse--extended hospital stays, increased morbidity and mortality, and the use of potentially more toxic and costly antimicrobial agents--require new strategies to prevent the spread of resistant organisms and to limit future resistance.