The natural calcium-regulating hormone 1α,25-dihydroxyvitamin D3 (1,25D3) is a secosteroid that offers organic chemists many sites for modifying structural and / or functional groups. Such modifications alter the chemistry, stereochemistry, and biological properties of the natural hormone. The resulting deltanoids (vitamin D analogs) have been used in the past two decades as molecular probes to investigate structure-function relationships based on their interactions with proteins that regulate deltanoid biostability (catabolic enzymes of the vitamin D endocrine system and vitamin D binding protein) and deltanoid transduction of biological activities (nuclear and membrane receptors). In this review we will focus on structural modifications of 1,25D3 that selectively modulate the nuclear vitamin D receptor (VDR). We will discuss the structural requirements and modifications that create analogs with greater potency and efficacy than the natural hormone (superagonists). We will also identify the structural features of an emerging group of noncalcemic selective agonists and describe the pharmacokinetic properties and VDR-mediated actions that promote their tissue- and gene-selective responses. In addition, we will speculate on the possible structural requirements for vitamin D antagonists. We will also examine the evidence from studies in cell-free systems, in culture and in vivo that explain the mechanisms for the distinct actions of each group of analogs, with special emphasis on the relationship between their mode of interaction with the VDR and the molecular and cellular outcome of these interactions. Finally, we will describe the current and potential use of these selective modulators of the VDR for treatment of human diseases such as osteoporosis, cancer, and secondary hyperparathyroidism.