1alpha, 25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the biologically active form of vitamin D, is an important hormone that is critically required for the maintenance of mineral homeostasis and structural integrity of bones. 1,25-(OH)2D3 accomplishes this by facilitating calcium absorption from the gut and by a direct action on osteoblasts, the bone forming cells. Apart form its classical actions on the gut and bone, 1,25-(OH)2D3 and its synthetic analogs also possess potent anti-proliferative, differentiative and immunomodulatory activities. 1,25-(OH)2D3 exerts these effects through vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the superfamily of steroid/thyroid hormone/retinoid nuclear receptors. The presence of VDR in various tissues other than gut and bone, along with their ability to exert differentiation, growth inhibitory and anti-inflammatory action, has set the stage for therapeutic exploitation of VDR ligands for the treatment of various inflammatory indications and cancer. However, the use of VDR ligands in clinic is limited by their major dose-related side effect, namely hypercalcemia/hypercalciuria. Efforts are being undertaken to develop vitamin D receptor modulators (VDRMs) that are tissue-selective and/or gene-selective in their action and these ligands may exhibit increased therapeutic indices. This review explores the recent advances in VDR biology, non-secosteroidal VDR ligands and the current and potential clinical applications of VDR ligands in inflammation and cancer.