A poor vitamin D status has been associated with several autoimmune diseases, including multiple sclerosis (MS). The receptor for the biologically active metabolite of vitamin D appears to be a key player in these associations, not only as a mediator of the biological effects of vitamin D, but also as a mediator of the regulation of vitamin D metabolism itself. In this concise review, we will discuss the mostly investigated genetic polymorphisms of the vitamin D receptor (VDR), and their consequences for VDR functionality and immune regulation. Next, we will discuss the association of these polymorphisms with MS, and their relation with vitamin D metabolism. We conclude that polymorphisms of the VDR have major effects on vitamin D function and metabolism, and should therefore be assessed in studies on vitamin D and MS.