Although most patients who report a history of drug allergy are not truly allergic, this article focuses on those individuals with confirmed drug hypersensitivity. Desensitization is an immunologic method that allows allergic patients to receive the sensitizing drug safely. Classically, the procedure is applied in IgE-mediated reactions, but its use has been extended to other drug reactions. The most common clinical scenarios wherein desensitization may be needed are reviewed. The discussion includes rapid desensitization of patients with IgE-mediated allergies to penicillin and other classes of antibiotics, and sulfonamide desensitization of HIV-positive patients.