Vitamin D is a secosteroid, in which the B ring of the steroid structure is ruptured. The active form of vitamin D, 1α, 25-dihydroxyvitamin D3 [1,25 (OH) 2D3], regulates numerous physiological and pharmacological processes, including bone and calcium homeostasis, cellular growth and differentiation, immunity, and cardiovascular function, through binding to the vitamin D receptor (VDR), a member of the nuclear receptor superfamily. VDR ligands are promising in the treatment of bone and mineral disorders, cancer, autoimmune disease, and cardiovascular disease. However, the calcemic effect of vitamin D derivatives has limited their clinical application. Recently, nonsecosteroidal VDR modulators (VDRMs) have been developed. Several VDRMs have better therapeutic efficacy when compared to 1,25 (OH) 2D3 in experimental models of cancer and osteoporosis with less induction of hypercalcemia. Analysis of crystal structures reveals that nonsecosteroidal VDRMs bind to VDR in a position similar to 1,25 (OH) 2D3 and that hydrogen bond interactions between ligands and VDR are important for VDR transactivation. Pharmacokinetics of nonsecosteroidal VDRMs may be related to their less calcemic effect. Nonsecosteroidal VDRMs can induce VDR conformation distinct from that by 1,25 (OH) 2D3, likely leading to selective gene expression. Although the potential risk of unexpected adverse effects needs be considered, further development of nonsecosteroidal VDRMs should expand the possibility of VDR-targeted approaches.