This chapter focuses on the evidence for metabolic and clinical effects of cobalamin and folate interactions in the light of improved folate status on a global level due to the widespread fortification of cereal based products with folic acid and to folic acid supplement use. The biochemical consequences of cobalamin deficiency are twofold; impaired nucleotide synthesis leading mainly to megaloblastic anaemia, and hypomethylation leading to neuropathy. Cobalamin deficiency is widespread in parts of the world where low amounts of animal-foods are consumed for religious, cultural, or economic reasons. Folic acid fortification and periconception supplement use may not be sufficient to prevent neural tube defects-affected pregnancies in the presence of cobalamin deficiency. Severe cobalamin deficiency is characterised by subacute combined degeneration of the spinal cord, peripheral neuropathy, and psychiatric disorders. Affective disorders, peripheral neuropathy and neurological changes are found in both folate and cobalamin deficient subjects. The prevalence of cognitive impairment was lower in participants with normal cobalamin/high folate status.