Methionine adenosyltransferase (MAT) is the sole enzyme responsible for the biosynthesis of S-adenosylmethionine (SAMe), the principal biological methyl donor, precursor of polyamines and in the liver, precursor of glutathione. In mammals, two different genes, MAT1A and MAT2A, encode for two homologous MAT catalytic subunits, 1 (forms either a dimer MAT III, or tetramer MAT I) and 2 (MAT II); while a third gene MAT2B, encodes for a regulatory subunit that regulates MAT II. Normal differentiated liver expresses MAT1A while all extrahepatic tissues express MAT2A. MAT2A is induced in the liver during periods of rapid growth and dedifferentiation. In human hepatocellular carcinoma (HCC), MAT1A expression is reduced while MAT2A and MAT2B are induced facilitating cancer cell growth. Patients with cirrhosis have decreased MAT1A expression and inactivation of MAT I/III, culminating in decreased SAMe biosynthesis. The consequences of chronic hepatic SAMe depletion are best illustrated by the Mat1a knockout (KO) mouse model, which is characterized by increased susceptibility to steatosis and oxidative liver injury, spontaneous development of steatohepatitis and HCC. Many signal transduction pathways are altered that contribute to HCC formation in this model. These studies illustrate involvement of SAMe in numerous cellular processes; some may be independent of methylation. SAMe has been shown to be chemopreventive against HCC in rodents fed different carcinogens. Part of this may be to prevent carcinogen-induced hepatic SAMe depletion and hypomethylation. In addition, SAMe is selectively pro-apoptotic in liver cancer cells and has anti-angiogenic properties. This should make SAMe an attractive agent for both chemoprevention and treatment of HCC. However, when tested in an in vivo HCC model, SAMe is effective in preventing HCC establishment but not as a treatment of already established HCC because the liver has compensatory mechanisms to prevent accumulation of SAMe to supraphysiologic levels. An alternate and more effective strategy is to enhance MAT1A expression in HCC. Although MAT genes are best known for SAMe biosynthesis, the fact that all three MAT genes are also found in the nucleus raises the possibility that they participate in other pathways. Indeed, MAT2B variants interact with HuR to influence its intracellular location and expression of HuR targets. Taken together, accumulating evidence show SAMe is more than just a methyl donor and MAT genes may participate in SAMe-independent intracellular processes.