Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that suppress both innate and adaptive immune responses through multiple mechanisms. In recent years, much of our knowledge of the function of MDSCs has come from cancer studies. However, a few recent advances have begun to characterize MDSCs in feto-maternal immune cross-talk. The microenvironment at the fetal-maternal interface is a complex milieu of trophoblasts and maternally-derived cells, which are biased to tolerogenic and Th2-type responses. Current data reveal that MDSCs accumulate at the fetalmaternal interface in healthy pregnancies. Yet, little is known about how MDSCs develop and why the response of MDSCs is heavily granulocytic. In this review, we discuss recent findings on the molecular mechanisms that regulate the expansion and function of MDSCs, in addition to various roles of MDSCs implicated in the modulation of feto-maternal immune cross-talk. Understanding the roles of MDSCs in inducing maternal-fetal tolerance, which is compromised in patients suffering from pregnancy complications, including preeclampsia, intrauterine growth restriction, spontaneous abortion, and preterm birth, we thus propose that the immunomodulatory activity of MDSCs should be carefully considered for the therapeutic approaches targeting pregnancy complications.