Drug provocation test (DPT) is necessary to diagnose most drug hypersensitivity reactions (HSRs) due to decreased sensitivity of skin testing even when combined with in-vitro tests in immunonologic drug HSR and limited availability of these tests in nonimmunologic reaction. We review the principles and controversial issues of DPT, and recent studies using DPT as a diagnostic tool.DPT is recommended in the diagnosis of HSR to β-lactams, as well as other drug classes [such as acetylsalicylic acid-NSAIDs (ASA-NSAIDs), non-β-lactams antibiotics, heparin, glucocorticoids, and local anesthetic agents]. In view of the decreased sensitivity of skin testing, limited accessibility to new benzylpenicillin polylysine (PPL)/mixture of minor determinant (MDM) test reagents and limited availability of validated sensitive in-vitro tests, individuals who require DPT to β-lactams are increasing. The negative predictive value of allergologic work-up is very high, ranging from 94 to 98% for β-lactams and those reactions after negative tests are mostly nonimmediate and mild. Finally, DPT is recommended to ascertain tolerability of alternative compound when evaluating cross-reactivity among different classes of β-lactams, NSAIDs and glucocorticoids, and possibly iodinated contrast media.DPT is often needed when evaluating patients with suspected drug HSR. More studies regarding standardization of the various protocols are needed in order to increase its acceptance and adoption as a standard practice in the diagnostic algorithm for drug HSR.