A little over two decades ago, the vitamin D₃ activation pathway was elucidated and alfacalcidol arrived on the scene as a prodrug for active vitamin D₃, 1α, 25-dihydroxyvitamin D₃, 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 analogue 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 analogues, 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 an ointment for the treatment of psoriasis vulgaris, an intractable skin disease. The other analogue, ED-71, possesses a profile inverse to that of OCT and is now under clinical development as an oral preparation for treatment of osteoporosis. The present overview focuses on the search for and synthesis of OCT and ED-71. It also refers to methodology of searching next-generation analogues, exemplifying a new analogue, DD-281, based on the knowledge accumulated through process development of OCT and ED-71.