Children with multiple drug allergies are likely to require treatment with one or more of the drugs to which they may have had a reaction, when there is no alternate effective drug available. Detailed review of their history and/or use of appropriate diagnostic studies will help determine the potential safety of readministering the desired drug as well as the method for its readministration, most likely in the form of a drug challenge or desensitization. A practical approach to the diagnosis and treatment of children with multiple drug allergies is described in this review.