Drug-induced anaphylaxis remains a relatively infrequent event. However, penicillin and associated beta-lactam antibiotics remain a primary cause of anaphylaxis. Penicillin allergies are undoubtedly overreported, and patients with suspected penicillin allergy can be treated with antibiotic alternatives. Penicillin allergy skin testing is a simple and effective way to identify true penicillin allergy. Skin testing involves testing for both major and minor determinants and should be conducted in a facility with available life-support equipment. The commercial major determinant product, benzylpenicilloyl-polylysine, was removed from the market in 2004; this action compromised the ability of clinicians to evaluate a patient's likely response to penicillin therapy. Alternatives to skin testing include laboratory synthesis of major determinants, use of the radioallergosorbent test (RAST), or a combination of RAST and minor determinant skin testing. Patients with suspected penicillin allergy can undergo desensitization if they require penicillin therapy. The planned return of a commercial major determinant will hopefully resolve this issue.