Folate plays a key role in maintaining genomic stability and providing methyl groups for the formation of dTMP from dUMP which is required for DNA synthesis and repair and for the maintenance of methylation patterns involving cytosine or specific sites such as CpG islands. Under conditions of low folate, dUMP accumulates producing DNA strand breaks and micronucleus formation as a result of excessive uracil incorporation into DNA in place of thymine. Methylenetetrahydrofolate reductase (MTHFR) is an important folate metabolizing enzyme that catalyzes the irreversible conversion of 5,10-methylenetretrahydrofolate, which is the methyl donor for the conversion of dUMP to dTMP, into 5-methyltetrahydrofolate, which is the methyl donor for remethylation of homocysteine to methionine. Certain common polymorphisms within the MTHFR gene (C677T, A1298C) result in reduced enzymatic activity and have been associated with reduced risk for a variety of cancers such as acute lymphocytic leukemia, lung and colorectal cancer. These common polymorphisms are also associated with hyperhomocysteinemia that has been reported to be an increased risk factor for neural tube defects and cardiovascular disease. In this chapter, we consider the role that MTHFR plays in relation to folate metabolism and the possible contribution made in relation to certain important clinical outcomes.