Carcinoma of the colon is common and its incidence varies according to the geographical location and dietary habits. The aims of this paper are, first, to review the current epidemiological data on the incidence and mortality of colon cancer in postmenopausal women using hormone replacement therapy (HRT); second, to review the published data on the prevalence of estrogen receptors in healthy and malignant colonic tissue; and third, to examine the available evidence of gene silencing as applicable to this and other neoplastic conditions. Estrogen use confers overall protection, with a reduction in the incidence of colon adenoma and carcinoma of about 30%. Estrogen use reduces the colon cancer-related mortality. The risk of colon cancer is decreased among current and recent users of postmenopausal HRT but the molecular mechanisms involved remain unclear. Estrogen acts either on a single major transformation step in the oncogenetic process, or is involved in multiple events that avert the course of this transformation. Aberrant methylation of the CpG islands in the promoter regions of the estrogen receptor gene, as well as of other genes, is equivalent to the silencing of that gene, with the consequence of inactivation, or reduced expression, of a number of genes downstream, including tumor suppressor genes. This epigenetic mechanism, when reversed, suppresses the growth of cancer cells in vitro and in vivo. The ubiquitous distribution of the estrogen receptor genes and their isoforms, in a tissue-specific manner, opens new avenues for the understanding of cellular behavior in health and disease.