Optimal antibiotic duration balances adequate infection treatment against risks of prolonged exposure including antimicrobial resistance, C. difficile infection, adverse drug effects, and microbiome disruption. Multiple landmark trials have demonstrated that shorter antibiotic courses are non-inferior to traditional longer courses for many common infections. The IDSA/ATS 2019 guidelines recommend community-acquired pneumonia treatment for a minimum of 5 days, with extension only if the patient has not achieved clinical stability (temperature ≤37.8°C, HR ≤100, RR ≤24, SBP ≥90, SpO2 ≥90%, ability to take oral intake, and normal mentation). Procalcitonin-guided antibiotic discontinuation in ICU patients has been shown to reduce antibiotic duration by 2-3 days without increasing mortality, as procalcitonin levels decline with resolution of bacterial infection. The concept of treating until clinical response plus a fixed short course is replacing arbitrary prolonged durations for most infections.