Background: Antibiotic allergies, especially penicillin, are the most frequent drug allergy listed in the medical record. Proactive evaluations of antibiotic allergies, particularly penicillin allergies, have been recommended by various specialty societies. Objective: To review the history of the discovery of penicillin, implications of the penicillin allergy label, various delabeling strategies as well as a brief overview of the approach to cephalosporin, fluoroquinolone, and macrolide allergy. Methods: Recent studies on penicillin allergy delabeling and on cephalosporin and fluoroquinolone allergies were reviewed. Results: Although Alexander Fleming is often solely credited with the discovery of penicillin, other scientists were critical to the development of penicillin as a life-saving antibiotic. The vast majority of patients with a penicillin allergy label are not allergic; however, this label results in increased morbidities and mortality. A variety of penicillin delabeling strategies can be used in both the outpatient and the inpatient settings. The role of direct penicillin challenge in patients at low risk is emerging and is the method of choice for children. Patients with an unconfirmed penicillin allergy have a low risk of reacting to cephalosporins. The R1 side chain largely dictates cephalosporin allergy and cross-reactivity. Drug challenge is the preferred method for evaluation of both fluoroquinolone and macrolide allergy. Conclusion: Multiple effective methods are available to delabel patients of common antibiotic allergies. Delabeling patients in a proactive manner can reduce patient morbidity.