Clinicians commonly encounter patients with a history of allergy to penicillin and other beta-lactam antibiotics, since about 10% of the population reports such an allergy. At the same time, it is known that about 90% of these patients are not truly allergic and could safely receive beta-lactam antibiotics. Instead, these patients are treated unnecessarily with alternate broad-spectrum antibiotics, which increases costs and contributes to the development and spread of multiple drug-resistant bacteria. In the case of penicillin, relevant allergenic determinants that elicit immune responses are known. Hence, validated diagnostic skin testing to detect the presence of drug-specific IgE antibodies is available. For non-penicillin beta-lactams, the immunogenic determinants that are produced by degradation are unknown, and diagnostic skin testing is of more limited value. Ideally, patients with a history of penicillin allergy should be evaluated when they are well and not in immediate need of antibiotic therapy. Patients who are found to be penicillin skin test-negative may be safely treated with all beta-lactam antibiotics. Penicillin skin test-positive patients should only receive a penicillin-class antibiotic via rapid desensitization, and only in cases when an alternative agent cannot be substituted. Penicillin skin test-positive patients may be safely treated with monobactams. The extent of allergic cross-reactivity between penicillin arid cephalosporins/carbapenems is uncertain; therefore penicillin skin test-positive patients should only receive these antibiotics via cautious graded challenge or desensitization. Identification of patients who erroneously carry a label of beta-lactam allergy leads to improved utilization of antibiotics and slows the spread of multiple drug-resistant bacteria.