Colon cancer remains a significant global health concern. The impact of specific dietary components on colon tissue likely depends on a host of genomic processes that influence the growth, development, and differentiation of the epithelial cells at the colon crypt surface, where the balance between proliferation and differentiation is maintained possibly through the Wnt (beta-catenin/T-cell factor) signaling pathway. A loss of balance caused by either genetic mutations or environmental factors such as dietary habits can modulate the risk for the formation of aberrant crypt foci and ultimately the development of colon cancer. Evidence exists that butyrate reduces the number and the size of aberrant crypt foci in the colon. Butyrate is a natural histone deacetylase inhibitor as well as a molecule involved with enhanced TGF-beta-induced SMAD3 phosphorylation, increased IFN-gamma-mediated apoptosis, and altered expression of the intestinal muc2 gene that is responsible for mucin synthesis. Other dietary components, such as vitamin D and (n-3) fatty acids, may regulate proliferative properties of colon progenitor cells as well as the differentiation of subcellular lineages. Although these findings are intriguing, there are uncertainties that remain to be resolved including the optimal exposure needed to bring about an effect, the appropriate timing of administration, and if nutrient-nutrient and nutrient-gene interactions determine the overall response. The expanded use of high-throughput technologies, knowledge about the expression of genes and protein fingerprints, and metabolomic profiling will assist in addressing these issues and ultimately in determining the physiological significance of bioactive food components as cancer protectants.