During pregnancy, the human body has to develop tolerance towards the fetus, as the fetus represents an immunologically “half-foreign” organism that under normal circumstances would be attacked by the mother’s immune system. This adaptation is achieved by the cross-talk between pregnancy-related hormones, the cells of the immune system, the placenta, and the fetus itself. The immune tolerance arising from this maternal immune adaptation to pregnancy can also have consequences such as infectious and autoimmune diseases. Some studies have suggested that pregnant women are more susceptible to microbial infections, including virus infections, but alternatively can result in a reduction in autoimmune diseases, such as multiple sclerosis. Type I Interferons (IFN-I) play a central role in the regulation of the immune response to viral infections and autoimmune diseases. However, little is known about the consequences of pregnancy on the IFN-I pathway. A better understanding of the interplay between pregnancy, sex hormones, and IFN-I will be important to therapeutically intervene in case of disease during pregnancy