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Drug allergy has been a research topic within the allergy field for decades. However, many drug reactions presumed to be of allergic nature are not and originate from different mechanisms. Drug-induced reactions can affect numerous organ systems, present with various symptoms, and have more than 1 mechanism of action. In this rostrum article, we want to give an overview of the different allergic and nonallergic reactions that can be expected with the (illicit) use of cannabis, cocaine, opioids, and alcohol. In addition, this article focuses on the different methods available to diagnose allergy related to these 4 drug types and highlight the pitfalls of nonallergic reactions or allergy "mimickers" complicating the diagnosis of true drug allergy. Finally, the impact on current medical practices and future research in support of the allergist in diagnosis and treatment of these medical problems is addressed., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)