Drug hypersensitivity reactions are a real challenge for allergologist practitioners. Variety of symptoms evoked by drugs and different pathomechanisms of the reactions make the diagnosis sometimes very difficult and the clinical thinking requires deep understanding of underlying immunological pathomechanisms. Moreover the new drug classes introduced to the treatment are evoking novel types of hypersensitivity reactions. The detailed clinical history is crucial to choose the proper way of further testing. In the case of confirmation of hypersensitivity reaction, the further step is to find the safe alternatives for culprit drug to desensitize the patient (if the culprit drug is unchangeable).