Poorly documented and often self-reported drug hypersensitivity (DH) is a frequent problem in daily clinical practice and has a considerable impact on prescription choices. Little is known about the natural history of true DH. The suspicion of DH starts on clinical grounds. When assessing a patient with a presumed DH reaction in the symptomatic phase, it is mandatory to look for severity signs and, after doing so, to update the risk/benefit balance of exploring the suspected drug(s) on a case-by-case basis. With the help of allergy tests and a careful approach, a firm diagnosis is often possible.