<qa>  What is the main reason for the lack of evidence for protection against colorectal cancer?There is strong biologic plausibility and animal experimental evidence for protection against colorectal cancer by calcium and vitamin D, calcium significantly reduced adenoma recurrence in a large clinical trial in humans yet the previously reported observational evidence, although generally supportive, is inconsistent, and the observational literature strongly supports protection from vitamin D. A close physiological relationship between calcium and vitamin D has long been known. Yet, other than a possible reduction of colorectal epithelial cell proliferation by calcium, the effects of calcium and vitamin D, individually or jointly, on the normal human colorectal epithelium remain unknown. There have been no clinical trials involving vitamin D individually or jointly with calcium related to colorectal cancer chemoprevention in humans. There are currently no generally accepted pre-neoplastic biomarkers of risk for colorectal cancer other than the possible exception of proliferation markers that, at best, have limited usefulness as individual markers. Based on recent advances in understanding the molecular basis of colorectal cancer, we developed a panel of newer, plausible, reliable, immunohistochemically detected biomarkers that provides molecular phenotyping of the normal appearing colorectal epithelium: 1 inflammation COX-2, 2 the expression of genes involved in the normal structure and function of the colorectal epithelium that have been found to be altered early in the two major colorectal carcinogenesis pathways APC, MSH2, MLH1, and 3 a more complete picture of the cell cycle events in colorectal epithelial crypt cells short and long-term proliferation: MIB-1 and telomerase; differentiation: p21; apoptosis inhibition and promotion: bcl-2, bax, and bak that has not yet been tested in a chemoprevention trial. 