Dendritic cells (DCs), the most potent antigen-presenting cells of the immune system, express nuclear receptors for 1,25-dihydroxyvitamin D(3) (VD3) and they are one of its main targets. In the presence of VD3, DCs differentiate into a phenotype that resembles semimature DCs, with reduced T cell costimulatory molecules and hampered IL-12 production. These VD3-modulated DCs induce T cell tolerance in vitro using multiple mechanisms such as rendering T cells anergic, dampening of Th1 responses, and recruiting and differentiating regulatory T cells. Due to their ability to specifically target pathological T cells, VD3-modulated DCs are safe and potentially more effective alternatives to currently available immunoregulatory therapies. While a number of considerations remain, including the establishment of a reliable quality control measure to ensure the safety and efficacy of VD3-DCs in vivo and the optimal frequency, dose, and route of DC administration to achieve therapeutic effects in humans, adoptive VD3-DC transfer represents one of the most promising approaches to future treatment of autoimmune diseases.