A compromised vitamin D status and nutritional calcium deficit are linked with sporadic colorectal cancer incidence. 25(OH)D(3) serum concentration is a major determinant of 1,25-dihydroxyvitamin D3 (1,25[OH](2)D(3)) synthesis in colonic mucosa, which expresses the vitamin D receptor and both the synthesizing (CYP27B1) and catabolic (CYP24A1) hydroxylases. Receptor-bound, 1,25(OH)(2)D(3) regulates proliferation, differentiation and apoptosis in an autocrine/paracrine manner. During early malignancy 1,25(OH)(2)D(3) synthesis is often enhanced to counteract hyperproliferation. In many advanced tumors, vitamin D catabolism surpasses synthesis. In vivo, expression and activity of CYP27B1 and vitamin D receptor are stimulated by (phyto)estrogens. Conversely, low nutritional calcium and folate enhance vitamin D catabolism. These insights could explain the lower colorectal cancer incidence in females, the chemopreventive potency of vitamin D and calcium against colorectal cancer, and the benefit of nutritional folate as a methyl donor for epigenetic regulation of the vitamin D system.