During pregnancy the maternal immune system is confronted with paternal allo-antigens. Therefore, fetomaternal rejection processes may represent a major cause of complications, such as preeclampsia, Hemolysis, Elevated Liver enzymes, Low Platelet (HELLP)-Syndrome, placental abruption and Intra-Uterine-Growth Restriction (IUGR). Several local mechanisms are known, which protect the fetus from maternal immune attack. In addition, mechanisms inducing peripheral immune tolerance to the fetus seem to be of equal if not even of greater importance for successful course of pregnancy. Such mechanisms may be the induction of CD25+CD4+ T regulatory cells, a specialized T-cell population which was shown not only to suppress autoaggressive immune responses but also to prevent graft rejection due to induction of transplantation tolerance. Other mediators influencing peripheral immune tolerance are soluble HLA (sHLA) class I and II molecules. Fetally derived sHLA molecules are able to block the allo-reactive cytotoxic T-cell response of the mother via T-cell-receptor binding. There is further evidence that sHLA class-I (HLA-A, -B, -C and -G) molecules inhibit NK-cell and cytotoxic T-cell activity through CD8 ligation. Thus, increased availability of sHLA-class-I molecules may have strong immune-suppressive effects and affect potentially maternal immune homeostasis. This review summarizes what is currently known about the induction of peripheral immune tolerance in pregnancy and discusses its relevance for the development of characteristic pregnancy-associated diseases.