Over the last 25 years roles have been established for vitamin D receptor (VDR) to influence cell proliferation and differentiation. For example murine knockout approaches have revealed a role for the VDR to govern mammary gland growth and function. These actions appear widespread as the enzymes responsible for 1α25(OH)2D3 generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings and functional data support the concept that local, autocrine and paracrine VDR signalling exerts control over cell fate decisions. In vitro and in vivo dissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells display de novo and acquired genetic and epigenetic mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance, and enhance efficacy of VDR-centred therapeutics.