Antibiotics are among the most widely and heavily prescribed drugs, but despite this, allergic reactions to most groups of antibiotics are relatively uncommon—especially when compared with the number and frequency of type 1 hypersensitivity responses to the β-lactams (ie, penicillins, cephalosporins, and, to a lesser extent, carbopenems). Still, there remains a steady flow of reports of allergic reactions to some topically used antibiotics (eg, rifamycin SV and bacitracin). Moreover, aminoglycosides (eg, neomycin and gramicidin) may be implicated more often than previously suspected. Despite advances in our understanding of the structural basis of the allergenicity of β-lactam antibiotics, the insights have not readily transferred into routine use to improve diagnoses of reactions to individual penicillins and cephalosporins. This remains a challenge in drug allergy, as does the need for further chemical, immunologic, and clinical research on cephalosporin breakdown products and the so-called multiple antibiotic allergy syndrome.