In the treatment of vesicoureteral reflux (VUR), the use of prophylactic antibiotics is most often the first treatment option in children with grades I-IV VUR. Both the overuse and misuse of antimicrobials have accelerated the appearance and spread of antibiotic resistance. There is a lack of controlled studies that address the role and efficacy of prophylactic antibiotic use in the VUR population. Physicians may also be pressured to prescribe antibiotic therapy by patients even in the absence of appropriate indications for use. However, patient reported compliance is often far lower than clinically documented compliance. The associated disadvantages of prophylactic antibiotic use include the development of antimicrobial resistance and patient noncompliance which begs for a re-evaluation of current management patterns of VUR. Considering questionable evidence supporting the use of traditional therapies, new innovations, including endoscopic injection, should be considered as an alternative.