Environmental triggers often work via signal transduction cascades that modulate the epigenome and transcriptome of cell types involved in the disease process. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system being characterized by a combination of recurring inflammation, demyelination and progressive loss of axons. The mechanisms of MS onset are not fully understood and genetic variants may explain only some 20% of the disease susceptibility. From the environmental factors being involved in disease development low vitamin D levels have been shown to significantly contribute to MS susceptibility. The pro-hormone vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) as a high affinity ligand to the transcription factor VDR (vitamin D receptor) and is a potent modulator of the epigenome at thousands of genomic regions and the transcriptome of hundreds of genes. A major target tissue of the effects of 1,25(OH)2D3 and VDR are cells of innate and adaptive immunity, such as monocytes, dendritic cells as well as B and T cells. Vitamin D induces immunological tolerance in T cells and reduces inflammatory reactions of various types of immune cells, all of which are implicated in MS pathogenesis. The immunomodulatory effects of 1,25(OH)2D3 contribute to the prevention of MS. However, the strength of the responses to vitamin D3 supplementation is highly variegated between individuals. This review will relate mechanisms of individual's vitamin D responsiveness to MS susceptibility and discuss the prospect of vitamin D3 supplementation as a way to extinguish the autoimmunity in MS.