Colorectal cancer is a major health problem worldwide. Epidemiological studies and work on experimental animals strongly suggest a protective effect of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) against colon neoplasia. 1,25(OH)2D3 is a pleiotropic hormone that has multiple actions in the organism. By binding to the widely expressed high affinity vitamin D receptor (VDR) it regulates the transcription rate of many genes. Other non-genomic effects of 1,25(OH)2D3 also appear to modulate the physiology of numerous cell types. Human normal and cancer colon epithelial cells express VDR and the key enzymes involved in 1,25(OH)2D3 synthesis and degradation and are, thus, responsive to the hormone. 1,25(OH)2D3 inhibits proliferation, induces differentiation and sometimes the apoptosis of human colon cancer cells. A great variety of mechanisms and signaling pathways are involved. Since VDR mediates most, if not all, 1,25(OH)2D3 actions, the control of VDR expression is a crucial aspect of 1,25(OH)2D3 biology. Here, the molecular mechanisms underlying the actions of 1,25(OH)2D3 are reviewed and the repression of the VDR gene by the transcription factor SNAIL in human colon cancer cells is discussed. Understanding these mechanisms may provide the basis for the potential use of this hormone and its non-hypercalcemic derivatives in the prevention and treatment of colon cancer.