Since the initial reports of penicillin and beta-lactam drugs causing allergic reactions, much has been elucidated regarding their pathophysiology and mechanism of action. Despite advances in testing for penicillin allergy, with IgE antibodies and skin tests available for the major and minor determinants of penicillin, these reactions remain a challenge to all physicians. They have characteristically been classified according to mechanism and time. Herein, the authors propose a classification system of penicillin allergy based on immunologic mechanisms.