The selection of perioperative antibiotic prophylaxis is challenging in patients with a history of penicillin allergy; as such, we present a literature review exploring current best practices and the associated supporting evidence, as well as areas for future research. Guidelines recommend the use of alternative agents in patients with an IgE-mediated hypersensitivity reaction, but those alternative agents are associated with worse outcomes, including an increased risk of surgical site infection, and higher cost. More recent data suggest that the risk of cross-reactivity between penicillins and cephalosporins, particularly cefazolin, is extremely low, and that cefazolin can be used safely in most penicillin-allergic patients. Studies have therefore explored how best to implement first-line cefazolin use in patients with a penicillin allergy label. A variety of interventions, including preoperative allergy de-labeling with incorporation of penicillin skin testing, use of patient risk-stratification questionnaires, and utilization of clinician algorithms to guide antibiotic selection intraoperatively, have all been shown to significantly increase cefazolin utilization without a corresponding increase in adverse events. Further studies are needed to clarify the most effective interventions and implementation strategies, as well as to evaluate whether patients with severe delayed hypersensitivity reactions to penicillin should continue to be excluded from receipt of other beta-lactams.