Folate plays a key role in the interactions between nutrition, fetal programming, and epigenomics. Maternal folate status influences DNA methylation, inheritance of the agouti phenotype, expression of imprinting genes, and the effects of mycotoxin FB1 on heterochromatin assembly in rodent offspring. Deficiency in folate and other methyl donors increases birth defects and produces visceral manifestations of fetal programming, including liver and heart steatosis, through imbalanced methylation and acetylation of PGC1-α and decreased SIRT1 expression, and produces persistent cognitive and learning disabilities through impaired plasticity and hippocampal atrophy. Maternal folate supplementation also produces long-term epigenomic effects in offspring, some beneficial and others negative. Deciphering these mechanisms will help understanding the discordances between experimental models and population studies of folate deficiency and supplementation.