Penicillin allergy has been extensively studied and has become a prototype for the study of allergic drug reactions. A significant number of patients have been incorrectly labeled as allergic to penicillin and therefore are denied this effective, nontoxic, and relatively inexpensive antibiotic. On the other hand, penicillin is by far the most common cause of allergic drug reactions and the leading cause of anaphylaxis in the United States. We have the tools to identify patients at a high risk of anaphylaxis from penicillin and should therefore be able to decrease the incidence of penicillin-related anaphylaxis and fatalities and to avoid denying the benefits of penicillin to a large segment of the population that has been labeled as penicillin allergic.