Folate and vitamin B12 are essential cofactors for the methionine/homocysteine cycle in the brain. These vitamins mediate the remethylation of homocysteine (HCY), which affects the production of the universal methyl donor, S-adenosylmethionine (SAM), in the brain among other organs. Acquired or inherited disorders in these metabolic pathways are associated with brain abnormalities and severe neurological symptoms that are mostly irreversible, even after providing the missing cofactors. This review discusses the relationship between brain and blood levels of key vitamins and metabolites related to one carbon metabolism.