Twenty-five years ago, alfacalcidol arrived on the scene as a prodrug of the active form of vitamin D3, calcitriol [1,25(OH)2D3] to remedy vitamin D3 deficiency. With the concurrent reported discovery of the differentiation-inducing effect of active vitamin D3, its diverse physiological effects have become appreciated and the research aiming to accentuate selected physiological effects by analog synthesis has made a fresh development. Our studies aimed particularly at separating the differentiation-inducing effect/cell growth-inhibitory effect and the calcemic effect of active vitamin D3 led to the development of two characteristic analogs, OCT and ED-71. OCT, characterized by its profound differentiation-inducing effect and modest calcemic effect, is currently in practical use as an injectable therapeutic agent for secondary hyperparathyroidism as well as in clinical settings as an ointment for the treatment of psoriasis vulgaris, an intractable skin disease. The other analog, ED-71, possesses a profile inverse to that of OCT and is now under phase III clinical development as an oral preparation for treatment of osteoporosis. OCT and ED-71 are considered second generation analogs developed from first generation analogs, 1,25(OH)2D3 and alfacalcidol used in vitamin D3 formulations. In further investigation of analogs having grater activity and biological differentiation than second generation analogs, we adopted in vivo bone effects as a target effect v. in vivo calcemic effects as a side effect using ovariectomized rats. From these studies, we are currently developing third generation analogs of 1,25(OH)2D3, such as DD-281, which is also discussed in the review.