The chlorinated methanes, particularly carbon tetrachloride and chloroform, are classic models of liver injury and have developed into important experimental hepatoxicants over the past 50 years. Hepatocellular steatosis and necrosis are features of the acute lesion. Mitochondria and the endoplasmic reticulum as target sites are discussed. The sympathetic nervous system, hepatic hemodynamic alterations, and role of free radicals and biotransformation are considered. With carbon tetrachloride, lipid peroxidation and covalent binding to hepatic constituents have been dominant themes over the years. Potentiation of chlorinated methane-induced liver injury by alcohols, aliphatic ketones, ketogenic compounds, and the pesticide chlordecone is discussed. A search for explanations for the potentiation phenomenon has led to the discovery of the role of tissue repair in the overall outcome of liver injury. Some final thoughts about future research are also presented.