Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system of presumed autoimmune origin. Intriguingly, pregnancy in female MS patients is associated with a substantial decrease in relapse rate. However, post-partum the relapse rate increases in a rebounding fashion above the rate seen before pregnancy. Wide gaps remain in our understanding of the biological mechanisms underlying these pregnancy-related effects in MS patients. To date, most attempts to explain MS disease amelioration during pregnancy have focused on levels of circulating hormones with immunomodulatory properties such as estrogens and global shifts in systemic maternal immune cell composition. However, recent advances in our understanding of feto-maternal tolerance have provided evidence that fetal antigens directly interact with the maternal immune system. This results in specific immunomodulation such as fetal-antigen-dependent induction of regulatory T cells. Thus, the "shaping" of maternal immune responses by fetal antigens may represent an endogenous pathway by which antigen-specific immunomodulation might also contribute to reinstalling tolerance to autoantigens in MS. Reproductive immunology therefore has great potential to provide insights into MS immunopathogenesis and highlight novel avenues for treatment of MS and other autoimmune diseases.