Vitamin D is a potent immune modulator, keeping the T-cell compartment in a more tolerogenic state. Multiple sclerosis (MS), a disease in which an autoreactive T-cell response contributes to inflammation in the central nervous system, has been associated with vitamin D deficiency. The effects of vitamin D on the immune system are believed to be an important driver of this association. In this chapter, we elaborate on vitamin D as a modulator of the T-cell response. This discussion will be placed in the perspective of MS as a T-cell-mediated disease and in the perspective of the numerous association studies on vitamin D deficiency and multiple health outcomes. We conclude that there is a firm experimental and epidemiological basis supporting the model of vitamin D as a physiological immune modulator, on which intervention studies assessing clinical and immunological outcome measures should be designed.