Collectively known as one-carbon metabolism (OCM), both the folate and methionine cycles are highly regulated to meet cellular demands. These cycles are key in the production and recycling of methyl groups to be used in many essential cellular processes such as the production of nucleotides, as well as S-adenosyl-l-methionine (SAM) the global methyl donor for DNA, RNA, and post translational modifications. Within the folate cycle, 5,10-methylenetetrahydrofolate is the main species through which methyl groups enter OCM. Therefore, 5,10-methylenetetrahydrofolate reductase (MTHFR), which reduces 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate, is the central enzyme that directs methyl groups for use within the methionine cycle. MTHFR is an enzyme found in all domains of life, but unlike in prokaryotes, eukaryotic MTHFR activity is highly regulated by the level of SAM, to balance the one-carbon needs of the cell. In this perspective, we review the catalytic mechanism of MTHFR, evolutionary differences, and the regulatory mechanisms that have evolved to alter its activity. We also discuss recent structural findings that reveal a unique mechanism for inactivation by SAM as a feedback loop and its consequences for understanding inherited MTHFR deficiency.