1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) interacts with the Vitamin D(3) receptor (VDR) to modulate proliferation and apoptosis in a variety of cell types, including breast cancer cells. In this review, we discuss three issues related to the role of the VDR in growth control: first, whether mammary glands lacking VDR exhibit abnormal growth; second, whether the VDR is essential for induction of apoptosis by 1,25(OH)(2)D(3); and third, whether VDR up-regulation can sensitize cells to 1,25(OH)(2)D(3). Studies from our laboratory have demonstrated that mammary glands from VDR knockout (VDR KO) mice exhibit accelerated growth and branching during puberty, pregnancy and lactation as compared to wild-type (WT) mice. In addition, involution after weaning, a process driven by epithelial cell apoptosis, proceeds at a slower rate in VDR KO mice compared to WT mice. Using cells isolated from VDR KO and WT mice, we report that both normal and transformed mammary cells derived from WT mice are growth inhibited by 1,25(OH)(2)D(3), however, cells derived from VDR KO mice are completely unresponsive to 1,25(OH)(2)D(3). In human breast cancer cells, we have identified a variety of agents, including steroid hormones, phytoestrogens and growth factors, that up-regulate VDR expression and enhance sensitivity to 1,25(OH)(2)D(3)-mediated growth inhibition. Collectively, these studies support a role for 1,25(OH)(2)D(3) and the VDR in negative growth regulation of both normal mammary gland and breast cancer cells.