The activated form of vitamin D, 1,25-dihydroxyvitamin D3, has not only a central role in bone and calcium metabolism, but also has important general effects on cell proliferation and differentiation. Moreover, 1,25-dihydroxyvitamin D3 behaves as a paracrine factor in the immune system as it can be produced by monocytes and has potent actions on all the cellular components of the immune defence system. In recent years, this new physiological role has been studied intensively both in terms of research and with the purpose of exploiting this action in a (pre)clinical setting. Indeed, through chemical alterations of the parent molecule, new substances have been created, called vitamin D analogues. Some of these molecules share the immunological effects of the mother compound, but have decreased effects on calcium and bone metabolism. This makes them potentially useful in clinical practice as immunomodulatory drugs. In the present review, we summarize the data on the in-vitro immune effects of 1,25-dihydroxyvitamin D3 and its analogues and demonstrate that these compounds have clear in-vivo immune modulating properties in the prevention of spontaneous and allergic autoimmune diseases and in the prevention of graft rejection.