Since its discovery in 1931 by Lucy Wills, and its first isolation in 1941 by Mitchell, Snell and Williams, our understanding of the fascinating world of folic acid and one-carbon metabolism, and its role in health and disease, has come a long way. However, there is still much to do in perfecting methods to measure folate bioavailability, and status, with a high degree of precision and accuracy. Future examination of the relationships of common gene polymorphims involved in folate bioavailability (folate polyglutamate deconjugation and carrier-mediated absorption) and one-carbon metabolism (methylation cycle, folate cycle and DNA synthesis/repair) to folate status, morbidity, mortality and longevity, need to be considered concurrently rather than as a series of individual associations, as has been the usual practice.