The extensive use of antibiotics in long-term–care facilities has led to increasing concern about the potential for the development of antibiotic resistance. Relatively little is known, however, about the quantitative relation between antibiotic use and resistance in this population. A better understanding of the underlying factors that account for variance in antibiotic use, unexplained by detected infections, is needed. To optimize antibiotic use, evidence-based standards for empirical antibiotic prescribing need to be developed. Limitations in current diagnostic testing for infection in residents of long-term–care facilities pose a substantial challenge to developing such standards.