Folate and choline are water-soluble micronutrients that serve as methyl donors in the conversion of homocysteine to methionine. Inadequacy of these nutrients can disturb one-carbon metabolism as evidenced by alterations in circulating folate and/or plasma homocysteine. Among common genetic variants that reside in genes regulating folate absorptive and metabolic processes, homozygosity for the MTHFR 677C > T variant has consistently been shown to have robust effects on status markers. This paper will review the impact of genetic variants in folate-metabolizing genes on folate and choline bioefficacy. Nutrient-gene and gene-gene interactions will be considered along with the need to account for these genetic variants when updating dietary folate and choline recommendations.