The mechanism of carbon tetrachloride (CCl₄)-induced hepatotoxicity, especially necrosis and fatty liver, has long been a challenging subject of many researchers from various fields over the past 50 years. Even though the mechanisms of tissue damages are different among chemicals and affected tissues, CCl₄ has played a role as a key substance of tissue injury. A number of studies have been conducted and various hypotheses have been raised. As a result, several important basic mechanisms of tissue damages have emerged, involving metabolic activation, reactive free radical metabolites, lipid peroxidation, covalent binding and disturbance of calcium homeostasis. Recent studies also revealed inflammation and regeneration as important modification factors in the tissue injury. The author attempted to summarize the history of CCl₄ research with some emphasis on the experiments done by the author and his colleagues. Their studies with isolated perfused rat liver suggest that covalent binding of CCl₄ metabolites rather than lipid peroxidation has a significant role in the production of centrilobular necrosis following CCl₄ administration. Further studies are necessary to unveil detailed mechanisms of hepatocyte necrosis induced by CCl₄.