Various protocols are being followed for endophthalmitis prophylaxis in cataract surgery, and this subject continues to be a matter of debate. We summarize the most recent evidence-based studies on this topic with additional stress on intracameral (IC) antibiotic prophylaxis. Here, we discuss several large, international clinical studies which discuss the efficacy, adoption, safety, cost, and newer trends in antibiotic prophylaxis. Majority of these studies report a significant reduction in endophthalmitis rates with IC antibiotic prophylaxis. Efficacy data have been reported for IC cefuroxime, vancomycin, and moxifloxacin. Surgeons are now looking for alternatives to vancomycin for IC prophylaxis because of its association with the rare but sight-threatening complication of hemorrhagic occlusive retinal vasculitis. A recent large clinical study shows convincing efficacy with IC moxifloxacin prophylaxis. Two large studies have also reported significant endophthalmitis reduction following use of IC antibiotic prophylaxis, in eyes with posterior capsule tear which are at highest risk for infection. Except for one randomized controlled trial, there is a lack of prospective data on this subject; however, considering the complexity of performing such studies, surgeons have to rely on the mounting evidence from other recent big data studies. Availability of approved intraocular antibiotic formulations will see a much higher adoption in the future.