Adverse drug reactions are common, but only 6% to 10% are immunologically mediated. Unlike most adverse drug reactions, allergic drug reactions are unpredictable. Whereas some drug-induced allergic reactions may be easily classified into one of the four Gell and Coombs hypersensitivity categories, many others that appear to have an immunologic component cannot be classified because of our lack of mechanistic information. Theoretically, any drug can induce an immune response. However, some drugs are more likely to elicit clinically relevant immune responses than are others. Drugs in this category include antimicrobial drugs, anticonvulsants, chemotherapeutic agents, heparin, insulin, protamine, and biologic response modifiers. After a drug-disease connection is established, it must be determined whether the reaction was immunologically mediated. Subsequently, confirmatory tests, if available, should be used to determine the allergic status of the patient. If these tests are not available, a graded challenge or desensitization may be considered, depending on the type of clinical reaction previously demonstrated and the need for drug readministration. Education of the patient and primary care physician is an important component of patient management. (J Allergy Clin Immunol 2003;111:S548-59.)