Physicians often must select antibiotics for patients who are reported to have an antibiotic allergy. For penicillins, the sensitivity of penicillin skin testing for predicting serious allergic reactions is excellent. For other beta-lactam antibiotics, penicillin skin testing is useful for excluding the possibility of sensitivity to the beta-lactam ring. For other antibiotics, the patient history remains the most useful tool for determining whether a serious reaction is likely to occur with further drug exposure. The cross-reactivity between penicillins and second- or third-generation cephalosporins (excluding cefamandole) is probably no higher than is the cross-reactivity between penicillins and other classes of antibiotics. When a patient has a suspected immunoglobulin E-mediated antibiotic allergy, desensitization therapy should be considered, if the efficacy of alternate antibiotics is in doubt. For the treatment of serious infections, it is usually possible to safely administer the antibiotic of choice despite a history of possible antibiotic allergy.