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In this review article, we intend to summarize the diagnostic tools available for the study of drug hypersensitivity reactions to chemotherapy and biologicals, based on the experience and controversies of the main research groups leading the topic. Recent publications with large cohorts of patients reacting to these drugs are allowing for a better understanding of phenotyping, endotyping, and optimally managing these patients. There is a remarkable heterogeneity on the diagnostic and therapeutic approach among the different groups, and yet this has allowed for very interesting discoveries. Clinical history alone is insufficient for a diagnosis, but in vitro and in vivo biomarkers are essential for personalized management plans and precision medicine. Drug provocation testing is an essential tool and criterion standard. Despite heterogeneity, dedicated multidisciplinary drug desensitization program/unit, with dedicated space and personnel for their activities, have shown to be the optimal approach. In this acticle, we provide detailed information on diagnostics tools, with an specific focus on drug provocation testing. Looking forward, collaboration, standardization of techniques, and generalization of solidly established drug allergy teams in large hospitals are fundamental steps for the specialty of allergy in the twenty-first century.