The fluoroquinolones have become the leading class of antimicrobial agents prescribed to adults in the United States. Resistance of key pathogens to fluoroquinolones has developed rapidly in parallel with increased prescribing of these drugs. We describe our pharmacist-led antimicrobial stewardship program that focused on reducing inappropriate prescribing of fluoroquinolones, with the goals of limiting the development of resistance and improving patient outcomes. Core strategies were regular monitoring and reporting of resistance trends observed on institutional antibiograms, performing drug audits and related studies with intervention and feedback to prescribers, implementing an automatic parenteral-to-oral conversion program, establishing and implementing a β-lactam-based institutional guideline for empiric therapy, and educating prescribers. This successful program reduced empiric prescribing of fluoroquinolones by 30%, improved susceptibility for all antipseudomonal agents against Pseudomonas aeruginosa overall by 10%, and decreased mortality associated with P. aeruginosa infections by 2-fold. Our stewardship program clearly demonstrated that pharmacists can take on leadership roles to positively change antimicrobial prescribing at the institutional level and improve patient outcomes.