Folate plays an essential role in the metabolic regulation of amino acids and nucleic acids, and in one-carbon metabolism. Folate must be obtained from the diet, and supplementation is strongly recommended in populations at risk for deficiency due to specific conditions. Folic acid is the synthetic form of the vitamin, usually incorporated into foods and supplements. In the body, it must be reduced into the bioactive folate derivative (6S)5-MTHF by cell metabolism. Folate deficiency is related to many health issues such as neurological disorders and can increase cardiovascular disease risk. Women of childbearing age and pregnant women, as well as individuals with MTHFR polymorphism, are the main populations at risk for folate deficiency. Folate supplementation is widely used for fertility, for the inhibition of embryonal neural tube defects (NTDs) in pregnancy and is important for lowering homocysteine levels. (6S)5-MTHF supplementation during pregnancy is preferred over folic acid for its ability to bypass the block in folic acid metabolism linked to enzymatic polymorphism. The use of (6S)5-MTHF can overcome the concerns about the risk for deleterious effects of Unmetabolized Folic Acid (UMFA) related to the use of a supraphysiological dose of folic acid.