BACKGROUND Idiosyncratic drug-induced liver injury (DILI) is a rare, serious and sometimes fatal condition that lacks an effective clinical countermeasure. Polymorphisms of bioactivation/toxification pathways via the Phase I drug-metabolizing enzymes, Phase II detoxification reactions and Phase III excretion/transport, together with immunological factors, are predisposing factors for some DILI. METHODS This review focuses on the seminal role of hepatic drug metabolism in the idiosyncratic toxicity response and the potential role of genetic polymorphisms in specific drug-metabolizing enzymes or transporters. Furthermore, the article looks at recent developments for the assessment of those mechanisms, in order to avoid them in novel drug candidates that are still under development. Examples of proposed or confirmed metabolic mechanisms from the current literature for marketed or previously marketed drugs are summarized in detail. The contributions of Phase I, II and III and other enzymatic pathways in the idiosyncratic response are reviewed with particular emphasis on gene polymorphisms that might explain why some individuals respond in an aberrant manner. CONCLUSIONS Toxicologists continue to focus their efforts to define the idiosyncratic response at the biochemical and molecular levels. This has resulted in the development of some early drug screening tools based on such characteristics as the daily dose, metabolite covalent binding and polymorphisms in drug-metabolizing enzymes. While it will take years to fully assess the impact of these recently developed assessment tools, research on genetically based differences in hepatic metabolic pathways will continue, aided by the establishment of DILI registries for improved patient access.