The plethora of biological activities of 1,25(OH)(2)D(3) and its analogs suggests an enormous potential for vitamin D therapy in the treatment of hyperproliferative diseases (cancer, psoriasis), endocrine dysfunction (hyperparathyroidism), immune disorders (autoimmune diseases, transplant rejection), bone disorders (osteoporosis, Paget's bone disease). However, the therapeutic limitation of 1,25(OH)(2)D(3) is its calcemic and phosphatemic activities, since it can cause serious side effects such as hypercalcemia and hyperphosphatemia at super physiological levels. Therefore, numerous efforts have been made to find the new vitamin D analogs, that retain the therapeutically important properties of 1,25(OH)(2)D(3) but with greater selectivity, which allows more effective intervention with fewer toxic side effects. This review will focus on the biological activities of the 2-substituted analogs of 1,25(OH)(2)D(3). They were classified as 2α-, 2β-, 2,2-disubstituted analogs, and those with modifications in both the A-ring at the 2-position and the side chains. Their structure-activity relationships and binding features with the vitamin D receptor (VDR) were discussed.