There is strong evidence that most idiosyncratic drug reactions (IDRs) are immune-mediated and are caused by reactive metabolites of a drug rather than by the drug itself. Several hypotheses have been proposed by which a drug could induce an immune response. The major hypotheses are the hapten hypothesis and the danger hypothesis; however, the characteristics and spectrum of IDRs are different with different drugs, and this likely reflects mechanistic differences; therefore, no one hypothesis is likely to explain all IDRs. Some IDRs appear to involve epigenetic effects, direct activation of antigen-presenting cells, or disturbing the normal balance of the immune system. It has been suggested that many cases of idiosyncratic liver injury are not immune-mediated, and other mechanisms such as mitochondrial injury may be involved. It is essential that any hypothesis be consistent with the clinical characteristics of the IDR. Although the characteristics of most idiosyncratic liver injury do not suggest that mitochondria are the major target, it is quite possible that milder mitochondrial injury could stimulate an immune-mediated reaction. The observation that IDRs can vary widely among different drugs and different patients is most easily explained by an immune mechanism in which the target of the immune response is different.