Vitamin D receptor (VDR) agonists are well known for their capacity to control calcium and bone metabolism and to regulate growth and differentiation of many cell types. More recently, it has become clear that VDR agonists possess immunoregulatory properties and, in particular, pronounced protolerogenic activities. These agents have been shown to be effective in several models of autoimmune diseases and are the most used topical agents in the treatment of psoriasis, a Th1 and Th17 cell-mediated autoimmune disease of the skin, indicating their potential applicability in the treatment of a variety of autoimmune diseases. VDR agonists can act directly on T cells, but dendritic cells (DCs) seem to be their primary targets. A potentially very important activity of VDR agonists is their capacity to induce in vitro and in vivo tolerogenic DCs able to enhance CD4+CD25+ suppressor T cells that, in turn, inhibit effector T-cell responses. Novel data now show that VDR agonists selectively modulate tolerogenic properties in blood myeloid but not plasmacytoid DCs, shedding new light on the multifaceted immunoregulatory properties of these agents.