Acetaminophen (APAP) is one of the quantitively most consumed drugs worldwide. Although safe at therapeutic doses, intentional or unintentional overdosing occurs frequently causing severe liver injury and even liver failure. In the United States, 50% of all acute liver failure cases are caused by APAP overdose. However, only one antidote with a limited therapeutic window, -acetylcysteine, is clinically approved. Thus, more effective therapeutic interventions are urgently needed. Although APAP hepatotoxicity has been extensively studied for almost 50 years, particular progress has been made recently in two areas. First, there is now a detailed understanding of involvement of oxidative and nitrosative stress in the pathophysiology, with identification of the reactive species involved, their initial generation in mitochondria, amplification through the c-Jun N-terminal kinase pathway, and the mechanisms of cell death. Second, it was demonstrated in human hepatocytes and through biomarkers that the mechanisms of liver injury in animals accurately reflect the human pathophysiology, which allows the translation of therapeutic targets identified in animals to patients. For progress, solid understanding of the pathophysiology of APAP hepatotoxicity and of a drug's targets is needed to identify promising new therapeutic intervention strategies and drugs, which may be applied to humans. In addition to further refine the mechanistic understanding of APAP hepatotoxicity and identify additional drugs with complementary mechanisms of action to prevent cell death, more insight into the mechanisms of regeneration and developing of drugs, which promote recovery, remains a future challenge. 35, 718-733.