This chapter distills 10 landmark trials that reshaped everyday infectious-disease practice across viruses, bacteria, and mycobacteria. ACTT-1 established remdesivir as the first antiviral to shorten recovery in hospitalized COVID-19—most for patients on low-flow oxygen—while underscoring the need for combination therapy to affect mortality. MERINO was decisively practice-changing, showing higher mortality with piperacillin–tazobactam vs meropenem for ESBL bacteremia and cementing carbapenems as first-line in this setting. Two trials (POET and OVIVA) overturned dogma around prolonged IV antibiotics: carefully selected endocarditis, bone, and joint infections achieved noninferior outcomes with oral step-down, fewer line complications, and shorter hospital stays. In the CNS, the European dexamethasone study demonstrated that early steroids reduce death and unfavorable outcomes in adult bacterial meningitis—especially pneumococcal—when given before or with the first antibiotic dose. PROACT tempered enthusiasm for biomarker-driven prescribing, finding no reduction in antibiotic exposure with procalcitonin guidance in U.S. EDs practicing contemporary stewardship. Tuberculosis care advanced on two fronts: PREVENT-TB validated a short, once-weekly rifapentine–isoniazid regimen (3HP) for latent infection with higher completion and similar—or better—protection; NIX-TB delivered a transformative 6-month all-oral BPaL regimen for XDR/complicated MDR-TB, with rigorous toxicity monitoring. For C. difficile, fidaxomicin matched vancomycin for initial cure but significantly cut recurrences, reframing first-line therapy. Finally, CAP-START supported beta-lactam monotherapy for most non-ICU CAP, enabling narrower empiric coverage without sacrificing outcomes. Collectively, these studies promote shorter, safer, more targeted treatment—anchored in stewardship, earlier recovery, outpatient feasibility, and real-world applicability.