Cancer is fundamentally a genetic and epigenetic disease that requires the accumulation of genomic alterations that inactivate tumor suppressors and activate proto-oncogenes. In addition to genetic mutation or allelic loss, epigenetic gene silencing associated with DNA methylation is now recognized as an alternative mechanism by which tumor suppressor genes are inactivated. In gastrointestinal cancers, for example, DNA methylation frequently alters the activity in a number of important signaling pathways by silencing expression of genes encoding Wnt antagonists, negative Ras effectors and p53 targets. Indeed, the list of genes aberrantly methylated in cancer is growing, and methylation of a p53 target micoRNA gene has recently been demonstrated. Sites of DNA methylation could be promising markers and targets for risk assessment, early detection and treatment of cancer.