Rational design, chemical synthesis, structural analysis, molecular modeling and biological evaluation are reviewed for all the double point modified vitamin D analogs that have been developed as potential therapeutics over the last several years. The idea of double modifications was based on the 3D structure of the ligand binding domain of the model of the vitamin D receptor. It was recently proved that structural modifications in the two remote parts of the vitamin D molecule might have additive biological effects resulting in an increased functional activity and lowered calcemic side effect. Recent in vivo experiments clearly demonstrated the potential use of these analogs in new therapeutic areas such as autoimmune and hyper-proliferative diseases, including cancer and the systemic treatment of psoriasis. Although some of these analogs are already approaching clinical trials, the molecular mechanism of action and their improved efficiency still remain to be fully understood. In this review the key steps of the convergent synthetic strategies that combine the modified A-ring and the CD-ring fragment carrying the altered side-chain are presented. The advantages of using the natural alicyclic and acyclic precursors are demonstrated as well as all the modern synthetic methodologies used for combining structural fragments. The results of molecular mechanics modeling are critically examined as well as the advantages and limitations of the use of the models of vitamin D proteins for the docking experiments and the design of new analogs. The potential use of advanced structural approaches, including high resolution X-ray crystallography, is discussed as to the prospect of providing a better understanding of the observed activity of modified analogs. Biological profiles in vitro and in vivo for groups of analogs are presented in a new tabular form to illustrate structure activity relationships.