While about 10% of the population reports a history of penicillin allergy, studies show that 90% on more of these patients are not allergic to penicillins and are able to take these antibiotics safely. The main reason for this observation is that penicillin allergy is often misdiagnosed and when present wanes over time in most (but not all) individuals. Patients labeled penicillin-allergic are more likely to be treated with alternative antibiotics (such as vancomycin and quinolones), have higher medical costs, experience longer hospital stays, and are more likely to develop complications such as infections with vancomycin-resistant enterococcus and Clostridium difficile. Evaluation for specific IgE to penicillin can be carried out by skin testing. Ideally, penicillin skin testing should be performed with both major and minor determinants. The negative predictive value of penicillin skin testing for immediate reactions approaches 100%, whereas the positive predictive value is between 40 and 100%. The usefulness of in vitro tests for penicillin-specific IgE is limited by their uncertain predictive value. They are not suitable substitutes for penicillin skin testing. By identifying the overwhelming majority of individuals who can safely receive penicillin and penicillin-like drugs, we can improve the appropriateness of antibiotic therapy and clinical care outcomes.