Reduction of selenite to hydrogen selenide was shown to involve GSH, TPNH, and glutathione reductase. Rat liver microsomes contain a labile, arsenite-sensitive methyltransferase that converts the selenide to dimethylselenide using S-adenosylmethionine. Rat liver and kidney cytosol contain a 30,000 MW arsenite-insensitive methyltransferase that catalyzes the same reaction. In the absence of TPNH and glutathione reductase there is a small amount of H2Se formed non-enzymicallyby means of reduction by GSH. The reaction of glutathione with aliphatic and aromatic seleninic acids was studied as a model for the reaction mechanism of glutathione peroxidase, a selenoprotein. These results suggest that a 4-electron reduction of aromatic seleninic acids to the corresponding selenol derivative takes place and that such compounds then are oxidized by hydrogen peroxide, thus catalyzing GSH oxidation by hydrogen peroxide, in the same manner as glutathione peroxidase. Glutathione peroxidase spontaneously liberates low molecular weight forms of selenium, a portion of which appears to be an organic union of substantial non-polar character.