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The addition of a methyl group (CH3) to specific cytosines in mammalian DNA controls early development by regulating gene activity (reviewed in 1–12). DNA methylation is defined as an “epigenetic” modification that results in a heritable change in gene function without altering the primary DNA sequence itself. The requirement for a properly functioning DNA methylation system in mammals is best appreciated when observing the severe consequences that result when this system fails. Mutations in the enzymes controlling methyl group addition, the DNA methyltransferases (DNMTs), cause deficient or nonphysiologic DNA methylation patterns that interrupt normal development. For example, targeted deletion of DNMT1 in mice is lethal to developing embryos, while naturally occurring DNMT3B mutations may cause the ICF (immunodeficiency, centromere instability, and facial anomalies) syndrome in humans (13, 14). Also, deletion of MeCP2, a protein that binds to methylated DNA, results in a Rett syndrome-like neurodevelopmental disorder in mice (15, 16). These findings highlight the importance of DNA methylation in epigenetic control of early mammalian development. The role of DNA methylation following embryogenesis is not resolved. However, DNA methylation patterns have been determined for numerous genes in multiple types of human malignancy. One rationale for this effort has been that nonphysiologic methylation patterns could promote transformation of normal cells to malignant cells through disruptions in physiologic gene regulatory processes. For example, hypermethylation could lead to aberrant tumor suppressor gene silencing, while hypomethylation could lead to inap