The year 2016 marks the 25th anniversary of the seminal Medical Research Council (MRC) randomized trial that conclusively demonstrated a marked protection against the recurrence of a neural tube defect (NTD) affected pregnancy among previously affected mothers by the simple prophylactic treatment of folic acid supplements in the periconceptional period [1]. This trial and a contemporaneous Hungarian trial [2] that assessed the efficacy of multivitamins containing folic acid on the first occurrence of an NTD were the culmination of a decade of prior research, primarily led by the work of Professor Smithells in Leeds, United Kingdom. Smithells’s work strongly suggested that women entering pregnancy with deficiency or inadequate status of specific micronutrients might be predisposed to these congenital defects, and that multivitamin supplements, taken before and during the first trimester of pregnancy, might be protective. The work resolved well-established epidemiologic data on the prevalence and patterns of occurrence of NTDs suggesting that maternal nutrition was an important factor. In the 25 years since these seminal trials, many countries worldwide have introduced mandatory folic acid food fortification programs to reduce NTD occurrence; other countries have limited their official involvement to public health recommendations and promoting increased awareness of the benefits of folic acid. The fortification programs have had more success, but the worldwide prevalence of NTDs is still documented at more than 300,000 births per year, with great 124variation in prevalence from region to region and an unclear extent of underreporting [3]. Moreover, efforts to understand the molecular nature of the effect of folic acid in preventing NTDs have had little success, despite intense research.