A low vitamin D status and inadequate calcium intake are important risk factors for various types of cancer. Ecological studies using solar UV-B exposure as an index of vitamin D3 photoproduction in the skin found a highly significant inverse association between UV-B and mortality in fifteen types of cancer. Of these, colon, rectal, breast, gastric, endometrial, renal and ovarian cancer exhibit a significant inverse relationship between incidence and oral intake of calcium. In addition, lung and endometrial cancer as well as multiple myeloma are considered calcium and vitamin D sensitive. Studies on tissue-specific expression of the CYP27B1-encoded 25-hdroxyvitamin D-1alpha-hydroxylase and of the extracellular calcium-sensing receptor (CaR) have led to an understanding how locally produced 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and extracellular Ca2+ act jointly as key regulators of cellular proliferation, differentiation and function. Thus, impairment of antimitogenic, proapoptotic and prodifferentiating signaling from the 1,25(OH)2D3-activated vitamin D receptor (VDR) and from the CaR in vitamin D and calcium insufficiency has been implicated in the pathogenesis of the aforementioned types of cancer. 1,25(OH)2D3 and calcium interact in modulating cell growth in different ways: (i) Signaling pathways from the VDR and the CaR converge on the same downstream elements, e.g. of the canonical Wnt pathway; (ii) high extracellular calcium modulates extrarenal vitamin D metabolism in favor of higher local steady-state concentrations of 1,25(OH)2D3; (iii) 1,25(OH)2D3 may up-regulate expression of the CaR and thus augment CaR-mediated antiproliferative responses to high extracellular Ca2+. This can explain why combined supplementation is required for optimal chemoprevention of cancer by calcium and vitamin D.