Pregnancy is a unique immune state in which both mother and embryo/fetus tolerate and interact with one another through term, without interfering with the mother's native immunity. When the embryo is viable, it initiates maternal immune tolerance (IT)--ut not immune suppression. The balance is complex: some immune disorders are ameliorated during pregnancy, despite the presence of an "inflammatory" environment. We have identified a pregnancy viability biomarker--preimplantation factor (PIF)--secreted only by viable embryos, which helps to initiate this maternal tolerance and uterine receptivity. Using anti-PIF antibodies, we have detected PIF in the fetus and placenta. Beyond enhancing uterine receptivity locally, PIF has also been detected in maternal circulation, and may promote peripheral tolerance. In the fetus, PIF may help avoid a "graft-versus-host"-type reaction PIF exhibits unique potent immune-modulatory effects and its synthetic analogue has been shown to exert significant protection in diverse immune scenarios. Nontoxic, low-dose, short-term PIF administration has led to long-term effects in preclinical models of multiple sclerosis (MS), juvenile diabetes mellitus (JDM), and graft-versus-host disease (GVHD), in a manner enabling its translation into a clinical setting. Further investigation of this compound is warranted.