Folate is the term given to a family of water-soluble compounds that function in multiple coenzyme forms in the transfer of one-carbon units. The isolation, structure identication, and synthesis of folic acid that took place in the 1940s led to the widespread therapeutic use of this B vitamin for the treatment of megaloblastic anemia. During the next 50 years, the basic aspects of folate metabolism and the biochemical functions were investigated and the key role of folate coenzymes in one-carbon metabolism was established. Since the early 1990s, the links between folate intake and birth outcome or chronic disease risk were explored. One of the most important public health discoveries of this century is that daily supplemental folic acid taken periconceptionally signicantly reduces the risk of neural tube defects (NTDs). The conclusive evidence related to folic acid and NTD risk reduction led to the implementation of global public health policies including mandatory folic acid fortication in North America. The identication of genetic polymorphisms that affect the structure/function of folate-related enzymes and proteins has served as the catalyst for the ongoing search for links between these polymorphisms and increased risk for birth defects and chronic disease.