One-carbon metabolism involves the folate and methionine (Met) cycles that work in unison to support lipid, nucleotide, and protein synthesis, as well as methylation reactions and the maintenance of redox status. Methyltetrahydrofolate is utilized by Met synthase to couple the folate and Met cycles. Methionine may also be formed by the transformation of choline-derived betaine by betaine hydroxymethyltransferase. Within the Met cycle, S-adenosylmethionine is formed and used to synthesize phosphatidylcholine. Such actions are considered important for hepatic very-low density lipoprotein assembly and triglyceride secretion. Following methylation, homocysteine is formed and utilized to synthesize glutathione within the transsulfuration pathway, which scavenges reactive oxygen species. These biochemical complexities play a major role in the transition dairy cow that experiences a demand for compounds with a labile methyl group. Indeed, dietary methyl donor supplementation has merit when we consider research demonstrating improved lactation performance, and prevention of hepatic triglyceride deposition, inflammation, and oxidative stress with this feeding strategy. However, our understanding of methyl donor utilization and efficacy to maintain peripartal health deserves consideration within the context of fatty acid supply and metabolism. In non-ruminants, transmethylation-dependent phosphatidylcholine synthesis favors phosphatidylethanolamine enriched in very-long chain polyunsaturated fatty acids (PUFA). Because hepatic PUFA depletion is a feature of fatty liver in transition cows, inadequate hepatic PUFA concentrations may limit the ability of methyl donors to stimulate phosphatidylcholine synthesis and prevent steatosis. Moreover, fatty acid oversupply or composition may counteract the potential benefits of dietary methyl donor supplementation on redox homeostasis and immune status. Although work has focused on methyl donor co-supplementation (e.g., choline and Met), future studies should determine whether specific dietary fatty acid feeding regimens optimize methyl donor efficacy in the transition cow.