Acetaminophen overdose and idiosyncratic drug-induced liver injury (DILI) are the most commonly identified causes of acute liver failure (ALF) in the United States. Suspected acetaminophen hepatotoxicity can be effectively treated with N-acetylcysteine but still an estimated 500 patients die each year. Product labeling changes, dispensing restrictions, and reformulation of acetaminophen containing narcotic analgesics have been proposed to reduce the rising incidence of this preventable form of dose-dependent liver injury. In contrast, idiosyncratic DILI is not preventable due to our lack of understanding of host susceptibility and outcome factors. Patients with ALF due to DILI are difficult to diagnose and have a low likelihood of spontaneous recovery. Patients with severe idiosyncratic DILI should be urgently referred to a transplant center as there are no established medical treatments beyond drug discontinuation. Investigation of host variability in metabolic, regeneration, and immunological pathways may provide insights into the molecular basis of DILI as well as improved diagnostic and prognostic biomarkers.