To report historically evolving strategies (then and now) in prevention and management of endophthalmitis.A perspective on relevant topics in the prophylaxis and management of endophthalmitis.This is an author-selected review of studies leading to changes in strategies for endophthalmitis management over the last 100 years.The current perspective discusses the trends and strategies over the past century. Historically, 3 endophthalmitis time-periods have existed and include the pre-antimicrobial era, the predominantly systemic antimicrobial era, and the current intravitreal antimicrobial era. The management of endophthalmitis from different etiologies, including endogenous, postinjection, post-cataract surgery, and other anterior segment-related (eg, post-penetrating keratoplasty), bleb-associated, glaucoma drainage device-associated, and open globe injury-associated, are discussed. Specific etiologies may predict most common microbial causes and may guide differing management strategies. Pars plana vitrectomy offers theoretical advantages but is generally reserved for patients with more advanced disease.Despite advances over the past 100 years, endophthalmitis is an important sight-threatening complication. Timely management with the appropriate use of antimicrobial agents may optimize visual outcomes.