Hypersensitivity reactions to drugs have increased in the past 25 years due to increased exposures and availability of efficient, targeted, and personalized medications. Rapid drug desensitization is a clinical procedure that allows for the safe administration of a drug in patients with a history of such hypersensitivity reactions. Desensitization allows the continued use of first-line therapies, leading to higher efficacy of treatment, fewer side effects, cost-effectiveness, and increased quality of life and life expectancy of patients when compared with the use of second-line therapy. In this review, we discuss the who, what, where, when, why, and how of drug desensitization.