S-Adenosyl-L-methionine (SAMe) exerts many key functions in the liver, including serving as a precursor for cysteine, 1 of 3 amino acids of glutathione--the major physiologic defense mechanism against oxidative stress. SAMe is particularly important in opposing the toxicity of free oxygen radicals generated by various pathogens, including alcohol, which cause oxidative stress largely by the induction of cytochrome P4502E1 (CYP2E1) and by its metabolite acetaldehyde. SAMe also acts as the main methylating agent in the liver. The precursor of SAMe is methionine, one of the essential amino acids, which is activated by SAMe-synthetase (EC 2.5.1.6). Unfortunately, the activity of this enzyme is significantly decreased as a consequence of liver disease. Because of decreased utilization, methionine accumulates and, simultaneously, there is a decrease in SAMe that acquires the status of an essential nutrient and therefore must be provided exogenously as a supernutrient to compensate for its deficiency. Administration of this innocuous supernutrient results in many beneficial effects in various tissues, mainly in the liver, and especially in the mitochondria. This was shown in alcohol-fed baboons and in other experimental models of liver injury and in clinical trials, some of which are reviewed in other articles in this issue.