Many adverse drug reactions are mediated by the immune system. This can be because the therapeutic effect of the drug targets the immune system. For example, immunosuppressive drugs increase the risk of infections. It is paradoxical that some immunosuppressive drugs can lead to autoimmune reactions. Another mechanism by which drugs can cause an adverse reaction involves an idiosyncratic response to the drug such as an immune-mediated skin rash. These idiosyncratic drug reactions (IDRs) are difficult to study because of the paucity of valid animal models and their unpredictable nature. Therefore, much of our mechanistic knowledge of IDRs is based on inferences from the clinical characteristics of IDRs rather than on controlled mechanistic studies. In general, IDRs are associated with a delay between starting the drug and the onset of the adverse reaction, and the typical delay is different for different types of IDRs. In contrast, on rechallenge, there is usually a rapid onset of the adverse reaction, which is characteristic of an amnestic immune response. The absence of such a rapid response is usually considered evidence that an IDR is not immune-mediated; yet, there are immune-mediated IDRs that do not have an amnestic response. One possible reason for the lack of an amnestic response is if the IDR has a strong autoimmune component leading to deletion of autoimmune memory cells when the drug is withdrawn. Another interesting characteristic of IDRs is that there are many drugs that can cause different types of IDRs in different patients. A possible explanation is that although the immune response is induced by a drug, it is directed against an autoantigen, and interindividual differences in the immune repertoire determine which autoantigen and target organ are affected. Although testing these hypotheses represents a difficult challenge, the importance of these adverse reactions makes it a high priority.