Drug-induced immune reactions are an important burden for patients and health systems. They can be classified into immediate-drug hypersensitivity reactions (IDHRs) and delayed-DHRs (DDHRs) based on their phenotype. Drugs do not always behave as allergens and need to bind to proteins, forming adducts. Therefore, IDHRs can be classified as antigenic (IgE, and IgG mediated) and nonantigenic immune responses (complement activation-[CARPA], mas-related G-protein coupled receptor member X2 [MRGPRX2], cyclooxygenase [COX]-1 and cytokine release reactions [CRRs]). DDHRs are even more complex due to the different cell subsets and mechanisms involved, showing both antigenic and nonantigenic immune responses too. Since different endotypes result in similar phenotypes, the establishment of specific biomarkers is essential for an accurate diagnosis, with important relevance for the management of patients, as well as for risk stratification. The biomarkers of clinical utility are skin tests, specific IgE (sIgE), tryptase, and some HLA-DR genotyping. The diagnostic performance depends on the responsible drug. This review highlights that, unfortunately, most biomarkers have not gone beyond analytic or clinical validity. It is therefore important to set up multicentre translational studies to advance the validation process towards reaching a clinical utility phase.