A position paper by the European Network for Drug Allergy (ENDA), the European Academy of Allergology and Clinical Immunology (EAACI) interest group on drug hypersensitivity, defines drug provocation tests (DPTs) as ‘the controlled administration of a drug in order to diagnose drug hypersensitivity reactions’. The DPT is widely considered to be the ‘gold standard’ to establish or exclude the diagnosis of hypersensitivity to a certain substance, as it not only reproduces hypersensitivity symptoms, but also any other adverse clinical manifestation, irrespective of the mechanism. The DPT can be harmful and thus should only be considered after balancing the risk-benefit ratio in the individual patient. The ENDA position paper specifies two main indications for DPTs with the suspected compounds: 1. to exclude hypersensitivity in non-suggestive histories of drug hypersensitivity and in patients with non-specific symptoms, such as vagal symptoms under local anesthesia; 2. to establish a firm diagnosis in suggestive histories of drug hypersensitivity with negative, non-conclusive, or nonavailable allergologic tests. A positive DPT result optimizes allergen avoidance, while a negative one allows a false label of drug hypersensitivity to be removed. For these reasons, DPTs are often carried out to exclude a diagnosis of hypersensitivity to β-lactams when other allergologic tests are negative. DPTs are also performed when the sensitivity of allergologic tests for evaluating allergic reactions to certain drugs, such as non-β-lactam antibiotics, heparins, and glucocorticoids, is limited. On the other hand, DPTs are also performed to diagnose hypersensitivity reactions to nonsteroidal anti-inflammatory drugs in subjects with the cross-reactive pattern, because both skin tests and in vitro diagnostic methods are ineffective in such patients.