The activated form of vitamin D3, 1 alpha,25(OH)2D3, not only plays a central role in bone and calcium metabolism, but also has potent antiproliferative and prodifferentiating effects. Moreover, the combined presence of 25(OH)D3-1 alpha-hydroxylase, as well as the vitamin D receptor in several tissues introduced the idea of a paracrine role for 1 alpha,25(OH)2D3. By introducing chemical modifications into the flexible molecule 1 alpha,25(OH)2D3, a whole generation of vitamin D analogues was created. Due to a clear dissociation of the antiproliferative and prodifferentiating effects from calcaemic effects, these analogues can be used not only for the treatment of bone disorders but also for non-classical applications. In the present review, a summary is given on the use of the 1 alpha,25(OH)2D3 analogues for the treatment of psoriasis, cancer and immune disorders together with new insights in the mechanism of action of these analogues.