Idiosyncratic drug-induced liver injury (DILI) is ranked among the top most common etiologies of acute liver failure (ALF). It carries poor transplant-free survival. Pirfenidone is an anti-inflammatory and antifibrotic drug that is commonly used for the treatment of idiopathic pulmonary fibrosis (IPF). Hepatotoxicity due to pirfenidone is rare and generally manifests as a mild rise in serum aminotransferases. In this mini-review, we report an unusual case of idiosyncratic DILI due to pirfenidone presenting as ALF, with emphasis on the definition, classification, diagnostic criteria, histopathology, molecular markers, and treatment options for DILI and related ALF. A 77-year-old man with known Parkinson's disease and IPF presented with jaundice for 7 days and altered mental status for 4 days. His long-term medications included a levodopa/carbidopa combination with a recent addition of pirfenidone over the previous 1 month; there was no monitoring of liver function tests. The evaluation suggested features of acute liver failure with grade III hepatic encephalopathy, acute kidney injury, and metabolic acidosis. The diagnostic workup ruled out viral, toxic, ischemic, and other etiologies for acute liver failure. Based on a Roussel Uclaf Causality Assessment Method score of 7 and possible DILI-ALF, pirfenidone was withdrawn. He was evaluated for liver transplantation but was declined. Despite all supportive measures in intensive care, organ failure progressed and he succumbed to the illness on day 4. Postmortem liver biopsy revealed findings consistent with DILI (final Roussel Uclaf Causality Assessment score, 10). Conclusion: DILI-ALF carries poor prognosis, and liver transplantation should be considered early in the course. Characterization, reporting, monitoring, and labeling of pirfenidone-related hepatotoxicity is vital given its common use in IPF. (Hepatology Communications 2018;2:142-147).