The introduction of antibiotic therapy into medical practice has yielded substantial benefits for patients over the past 6 decades. However, the benefits of antibiotic use to individual patients come at a societal cost: the emergence of antimicrobial resistance (AMR) among bacterial pathogens. Once confined to the inpatient setting, resistant bacteria are now common community-acquired infections as well. Antibiotic use encourages the development and spread of antibiotic-resistant bacteria by at least two mechanisms: (1) by applying selective pressure, encouraging development of new strains of antibiotic-resistant bacteria, and (2) by eliminating normal bacterial flora in human hosts, which promotes colonization and spread of existing antibiotic-resistant strains. The increasing prevalence of antibiotic resistance has led to the use of more expensive and broad-spectrum antibiotics for empiric treatment of common outpatient infections, and increased morbidity and mortality among patients hospitalized with serious community-acquired infections. Reducing inappropriate use of antibiotics is a critical step in slowing the progression of current levels of resistance, and in preventing the emergence of new strains of antibiotic-resistant bacteria. Accomplishing this requires a two-part approach. First, the use of antibiotics in conditions for which these drugs provide little or no benefit must be reduced. Second, antibiotics prescribed for patients who do require antimicrobial therapy must be appropriately targeted, and inappropriately lengthy treatment courses should be shortened. In this fourth volume of the Closing the Quality Gap series, we critically analyze quality improvement strategies to reduce inappropriate antibiotic prescribing. We focus on interventions targeting antibiotic prescribing for acute illnesses in the outpatient setting, primarily acute respiratory infections (ARIs). Prescribing for acute conditions accounts for the majority of antibiotics dispensed in the US, and is thus likely to have the greatest influence on AMR patterns. We examined the effect of quality improvement strategies on antibiotic treatment (the decision to prescribe antibiotics for illnesses for conditions generally not requiring antibiotic therapy) and antibiotic selection (the choice of one antibiotic over another for illnesses requiring antibiotic treatment). Our review includes studies on the effect of prescribing-focused QI strategies on AMR, clinical outcomes, costs of prescribing, and patient satisfaction. We structured the review to address the following key threshold questions: 1. Are quality improvement strategies to improve outpatient antibiotic use effective? 2. What are the critical components of effective intervention strategies? 3. Which patients and conditions should be targeted in order to exert the maximal impact on antibiotic prescribing? 4. What are the limitations of current research in this field, and which areas require further study?