Multiple mechanisms are likely to be involved in the pathogenesis of alcoholic liver injury. The metabolism of alcohol by hepatocyte enzyme systems probably contributes to hepatotoxicity by generating reactive metabolites and oxygen species that damage vital molecules and tax hepatocyte defense mechanisms. However, these responses are generally not sufficient to kill hepatocytes, as demonstrated by observations that serious liver damage is infrequent in most humans and experimental animals that consume large amounts of alcohol for long periods of time. Indeed, work in animal models of alcoholic liver injury indicates that TNFa, a proinflammatory cytokine, is necessary for alcohol to injury the liver. However, this finding is also curious because TNFa does not usually kill hepatocytes. Thus, although the specific mechanisms remain poorly understood, it is likely that TNFa and ethanol cooperate to produce liver injury. Emerging evidence suggests that chronic alcohol consumption inhibits some of the protective and proliferative responses that normally occur in hepatocytes that have been exposed to TNFa. In addition, alcohol and TNFa also interfere with the actions of growth and viability factors, such as insulin. The cumulative effects of these processes cause hepatocyte death while impairing the liver's normally robust regenerative response, and then, serious liver damage occurs.