Epigenetic silencing is now recognized as a 'third pathway' in Knudson's model of tumor-suppressor gene inactivation in cancer and can affect gene function without genetic changes. DNA methylation within gene promoters and alterations in histone modifications appear to be primary mediators of epigenetic inheritance in cancer cells. For selected genes, epigenetic changes are tightly related to neoplastic transformation in colorectal cancers (CRCs). In the colon, aberrant DNA methylation arises very early, initially in normal appearing mucosa, and may be part of the age-related field defect observed in sporadic CRCs. Aberrant methylation also contributes to later stages of colon cancer formation and progression through a hypermethylator phenotype termed CpG Island Methylator Phenotype (CIMP), which appears to be a defining event in about half of all sporadic tumors. CIMP+ CRCs are distinctly characterized by pathology, clinical and molecular genetic features. Histone modifications, recently recognized as a 'histone code' that affects chromatin structure and gene expression also play an important role in the establishment of gene silencing during tumorigenesis. DNA methylation and histone H3 lysine 9 hypoacetylation and methylation appear to form a mutually reinforcing silencing loop that contributes to tumor-suppressor gene inactivation in CRCs. Understanding epigenetic alterations as a driving force in neoplasia opens new fields of research in epidemiology, risk assessment, and treatment in CRCs.