The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, is a secosteroid hormone that regulates calcium and bone metabolism, controls cell proliferation and differentiation, and plays an important role as an immunomodulator. Recent advances in understanding the mechanisms underlying 1,25(OH)2D3 immune actions expand the range of the therapeutic implications of 1,25(OH)2D3 and its analogs. This review will cover the current knowledge on vitamin D-mediated immunotolerance and recent advances in vitamin D-based therapies for the treatment of autoimmune disease and the prevention of graft rejection in renal transplantation. Initiation of vitamin D-based therapies at earlier stages of chronic kidney disease may impact the immune status of patients who progress to require dialysis or transplantation.