To aid the cataract surgeon's understanding of rational approaches to antimicrobial prophylaxis and place the European Society of Cataract & Refractive Surgeons (ESCRS) postoperative endophthalmitis study in perspective, a review was conducted of published and unpublished data on intracameral antibiotic use during cataract surgery and the antimicrobial efficacy, pharmacodynamics, ocular penetration, and safety of moxifloxacin. The ESCRS-sponsored study of postoperative endophthalmitis prophylaxis reported rates of presumed infectious postoperative endophthalmitis of 0.07% with intracameral cefuroxime treatment and 0.34% in control groups. Postoperative endophthalmitis after cefuroxime use was mostly due to cefuroxime-resistant gram-positive bacteria. Intracameral cefuroxime also requires extemporaneous compounding, has short-term stability, and carries a risk for hypersensitivity. Moxifloxacin, a fourth-generation fluoroquinolone, has potent and rapid bactericidal activity against the most common gram-positive postoperative endophthalmitis pathogens, has excellent ocular penetration after topical administration, and is available in a self-preserved ophthalmic formulation that has been shown safe and effective in preventing endophthalmitis when administered intracamerally in an animal model. Available data suggest that the optimum antibiotic regimen and route of delivery for cataract surgery antimicrobial prophylaxis require further study. Moxifloxacin offers many theoretical advantages that make it an attractive first-line choice for topical use and of interest for intracameral administration.