Antibiotics are among the most remarkable life-saving advances of modern medicine. However, when used incorrectly these medications pose serious risks for patients due to adverse effects and the potential to cause complicated infections, including those resistant to multiple antibiotics. This national database study found that more than half of all patients discharged from a hospital in 2010 received antibiotics during their stay. Many of these antibiotics were deemed to be unnecessary, and there was wide variation seen in antibiotic usage across hospital wards. A model accounting for both direct and indirect effects of antibiotics predicted that decreasing hospitalized patients' exposure to broad-spectrum antibiotics by 30% would lead to a 26% reduction in Clostridium difficile infection. The CDC recommends that all hospitals implement antibiotic stewardship programs, and this article provides core elements to guide these efforts. An AHRQ WebM&M commentary describes inappropriate antibiotic usage that resulted in a patient death. Dr. Alison Holmes spoke about infection prevention and antimicrobial stewardship in a recent AHRQ WebM&M interview.