Idiosyncratic adverse drug reactions (IADRs) encompass a diverse group of toxicities that can vary by drug and patient. The complex and unpredictable nature of IADRs combined with the fact that they are rare makes them particularly difficult to predict, diagnose, and treat. Common clinical characteristics, the identification of human leukocyte antigen risk alleles, and drug-induced proliferation of lymphocytes isolated from patients support a role for the adaptive immune system in the pathogenesis of IADRs. Significant evidence also suggests a requirement for direct, drug-induced stress, neoantigen formation, and stimulation of an innate response, which can be influenced by properties intrinsic to both the drug and the patient. This Perspective will provide an overview of the clinical profile, mechanisms, and risk factors underlying IADRs as well as new approaches to study these reactions, focusing on idiosyncratic drug-induced liver injury.