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Methyl groups are either obtained from the diet (labile methyl groups) or produced endogenously (methylneogenesis) via the one-carbon (C1-) metabolism as S-adenosylmethionine (SAM). The essential nutrients, folate and choline (through betaine) are metabolically entwined to feed their methyl groups into the C1-metabolism. A choline deficient diet in rats produces a 31-40% reduction in liver folate content, 50% lower hepatic SAM levels and doubling of plasma homocysteine. Similarly, folate deficiency results in decreased total hepatic choline. Thus, sufficient intakes of both folate and choline (or betaine) contribute to safeguarding the methyl balance in the body. A significant amount of choline (as phosphatidylcholine) is produced in the liver via the SAM-dependent phosphatidylethanolamine methyltransferase. Experimental studies using a diet deficient in several methyl donors have shown that supplemental betaine was able to rescue not only plasma betaine, but also plasma folate.Fasting plasma homocysteine concentrations are mainly determined by folate intake or status, while the effect of choline or betaine on fasting plasma homocysteine is minor. This appears to contradict the finding that approximately 50% of cellular SAM is provided via the betaine homocysteine methyltransferase (BHMT) pathway that uses dietary choline (after oxidation to betaine) or betaine to convert homocysteine to methionine and then SAM. However, it has been shown that the relative contribution of choline and betaine to the cellular methylation is better reflected by measuring plasma homocysteine after a methionine load test. Choline or betaine supplementation significantly lowers post methionine load homocysteine. Whereas, folate supplementation has a minor effect on post methionine load homocysteine concentrations. This review highlights the interactions between folate and choline and the essentiality of choline as a key player in C1-metabolism. We further address some areas of interest for future work.