1,25-dihydroxyvitamin D₃ (1,25D), the biologically active form of vitamin D_3, exerts anti-proliferative and pro-apoptotic effects in multiple transformed cell types, and thus the vitamin D signaling pathway represents a potential anti-cancer target. Although chronic treatment with 1,25D induces hypercalcemia, synthetic vitamin D analogs have been developed that inhibit tumor growth in vivo with minimal elevation of serum calcium. Furthermore, vitamin D is synthesized in skin exposed to ultraviolet (UV) light, and this route of vitamin D elevation is not associated with hypercalcemia. In this study, we examined whether enhancement of vitamin D status via exogenous (EB1089, a 1,25D analog) or endogenous (UV exposure) approaches could exert anti-tumor effects without hypercalcemia. We utilized mammary xenografts with differential vitamin D receptor (VDR) expression to examine whether the anti-tumor effects of either therapy are receptor-mediated. We present evidence that both EB1089 and UV exposure inhibit tumor growth via induction of growth arrest and apoptosis. These anti-tumor effects were only observed in xenografts containing VDR positive tumor cells; heterogeneous tumors containing VDR negative tumor cells and VDR positive stromal and endothelial cells were unresponsive to both therapies. No evidence for anti-angiogenic effects of EB1089 were detected in this model system. Neither EB1089 nor UV was associated with overt toxicity, but keratinocyte proliferation was increased in UV-exposed skin. These data provide proof of principle that UV exposure modulates tumor growth via elevation of vitamin D signaling, and that therapeutic approaches designed to target the vitamin D pathway will be effective only if tumor cells express functional VDR.