Drug hypersensitivity results from interactions between a pharmacologic agent and the human immune system. These types of reactions constitute only a small subset of all adverse drug reactions. Allergic reactions to medications represent a specific class of drug hypersensitivity reactions mediated by IgE. Immune-mediated drug reactions may be discussed generally in the Gell and Coombs classification system, a widely accepted conceptual framework for understanding complex immune reactions. However, some reactions involve additional, poorly understood mechanisms that are not easily classified. Identifiable risk factors for drug hypersensitivity reactions include age, female gender, concurrent illnesses, and previous hypersensitivity to related drugs. Drug hypersensitivity is a clinical diagnosis based on available data. Laboratory testing may be useful, with skin testing providing the greatest specificity. Treatment is largely supportive and includes discontinuation of the offending medication, symptomatic treatment, and patient education. Patients with penicillin allergy should avoid carbapenems, and caution should be used in prescribing cephalosporins in these patients. Reactions to radiocontrast media can be limited by pretreatment with prednisone, diphenhydramine, and either ephedrine or a histamine H2-receptor antagonist.