Recognition of foreign paternal antigens expressed in the semi-allogeneic fetus by maternal immune cells is a requirement for successful pregnancy. However, despite intensive research activity during the last decades, the precise mechanisms contributing to the acceptance of the paternal alloantigens are still puzzling and pregnancy remains a fascinating phenomenon. Moreover, most studies focused on the maternal and fetal contribution to pregnancy success, and relatively little is known about the paternal involvement. In the current review, we address the contribution of paternal-derived factors to fetal-tolerance induction. First, we discuss data suggesting that in both humans and mice, the female body gets prepared for a pregnancy in every cycle, also in regard to male alloantigens delivered at coitus. Then, we provide an overview about factors present in seminal fluid and how these factors influence immune responses in the female reproductive tract. We further discuss ways of paternal alloantigen presentation and identify the immune modulatory properties of seminal fluid-derived factors with a special focus on Treg biology. Finally, we highlight the therapeutic potential of seminal fluid in different clinical applications.