The isolated perfused rat liver and suspensions of isolated hepatocytes readily metabolize histidine but contrary to the liver in vivo do not form glucose. Formiminoglutamate was identified as a major product of histidine degradation in the isolated tissue preparations. The accumulation of formiminoglutamate was much diminished by the addition of physiological concentrations (0.1 m m) of l-methionine. No other protein amino acid had the same effect but l-ethionine was equally effective. Methionine, like other amino acids and low molecular cell constituents, is washed out of the liver cells on perfusion and on suspension in semi-synthetic media containing no amino acids. Addition of methionine restores the physiological tissue concentration. An accumulation of formiminoglutamate is already known to occur on histidine loading in vitamin B 12 deficiency. Thus the isolated liver preparations behave in this respect like the B 12-deficient liver in vivo. In vitamin B 12 deficiency the synthesis of methionine from homocysteine is impaired because of the cofactor function of vitamin B 12 in the methylation of homocysteine. The common feature of B 12-deficient liver and the liver preparations used is thus a deficiency in methionine. The degradation of formiminoglutamate involves the transfer of the formimino group to tetrahydrofolate and the conversion of the one-carbon unit to CO 2. An intermediate in this reaction is formyl tetrahydrofolate. The analysis of the methionine effect revealed that the release of CO 2 from formate by hepatocytes (which involves as an intermediary step the synthesis of formyl tetrahydrofolate) is also promoted by methionine or ethionine. The data are in accordance with the conclusion that the point of action of methionine is formyl tetrahydrofolate dehydrogenase which is activated by this amino acid. This activation may be looked upon as one of the key factors (there are others to which reference is made) in the regulation of folate metabolism and of methionine metabolism. Two pathways are open to the one-carbon units attached to tetrahydrofolate derived mainly from histidine, serine and glycine: either disposal by dehydrogenation to CO 2 or preservation for the supply of methyl groups for the regeneration of methionine from homocysteine, formyl groups in purine synthesis and of the one-carbon unit needed for the methylation of deoxyuridine monophosphate. Thus regulation of degradation versus preservation is necessary. This implies that there must be a flexible outlet disposing of surplus one-carbon units. Otherwise free tetrahydrofolate would disappear by complete conversion into its one-carbon derivatives. This outlet is the formyl tetrahydrofolate dehydrogenase reaction. The outlet must be open when there is excess one-carbon units over demand and blocked when the supply is limiting. The indicator of excess of supply is the concentration of methionine; the activation by methionine of formyl tetrahydrofolate dehydrogenase opens up the pathway by which the excess is degraded. In the case of methionine also regulation of degradation versus preservation is necessary. As methionine is an essential amino acid adequate amounts for protein synthesis and the methyl carrier function must be preserved while excess is removed to give energy and/or glucose. The branching point at which the fate of the carbon skeleton of methionine is decided is the stage of homocysteine. If this is not methylated it reacts with serine to enter the cystathionine pathway. The signal deciding the fate of homocysteine in favor of degradation is a decreased supply of methyl tetrahydrofolate. When the cell is saturated with methionine formyl tetrahydrofolate dehydrogenase becomes activated and this decreases the generation of methyl tetrahydrofolate so that homocysteine remains unmethylated and forms cystathionine. Thus the activation of formyl tetrahydrofolate dehydrogenase by methionine at the same time regulates the metabolism of one-carbon units and of methionine, by facilitating the irreversible disposal of one-carbon units and of the carbon skeleton of methionine. Whether activation of formyl tetrahydrofolate dehydrogenase by methionine is a direct effect of methionine on the enzyme or is brought about indirectly is an open question. This work started with an analysis of the observation that isolated liver preparations, contrary to the liver in vivo, form no glucose from histidine. It led to one major new observation, namely that the fate of the one-carbon units attached to tetrahydrofolate depends on the concentration of methionine. This finding proved relevant to the understanding of regulatory mechanisms, and so the work ended by arriving at new concepts about the regulation of the metabolism of methionine and of the one-carbon units handled by tetrahydrofolate. The results bear on several observations and concepts recorded in the literature, such as the methyl folate trap hypothesis.