Folate, and B vitamins, i.e. vitamin B_<12>, vitamin B_6 and vitamin B_2 are cofactors in the folate cycles and homocysteine metabolism, and inadequate status of these vitamins is associated with higher plasma homocysteine concentrations, which is a risk factor for atherosclerosis, cardiovascular disease, stroke, and cognitive impairment. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism can also affect plasma homocysteine level and is a genetic risk factor of those diseases and neural tube defects (NTDs). Individuals with the homozygous mutant (TT) genotype have a significantly higher homocysteine levels and lower folate levels in blood than those with the CC and CT genotypes. Plasma homocysteine level is responsive to intervention with folic acid and related B vitamins. Thus, high intakes of folate and B vitamins may be associated with a reduced risk of CVD, NTDs and cognitive impairment. The present review focuses on the gene-nutrient interaction, which is involved in the folate cycles and homocysteine metabolism, in the prevention of CVD, NTDs and cognitive impairment.