Acetaminophen (AAP) overdose and the resulting hepatotoxicity is an important clinical problem. In addition, AAP is widely used as a prototype hepatotoxin to study mechanisms of chemical-induced cell injury and to test the hepatoprotective potential of new drugs and herbal medicines. Because of its importance, the mechanisms of AAP-induced liver cell injury have been extensively investigated and controversially discussed for > 30 years. This review highlights recent new insight into intracellular events critical for liver cell death. In addition, the relevance of the inflammatory response is addressed, including cytotoxic and inflammatory mediators generated by activated inflammatory cells, that is, resident macrophages and lymphocytes as well as newly recruited blood-derived leukocytes. Inflammation is a critical component of the overall pathophysiology, not only as a potential factor that may aggravate cell damage, but more importantly as a vital response to limit cell injury, remove cell debris and promote regeneration.