A special interaction is established during pregnancy between the maternal immune system and fetal cells to allow the survival and the normal growth of the fetus. Fetal cells expressing paternal alloantigens are not recognized as foreign by the mother because of an efficient anatomic barrier and a local immunosuppression determined by the interplay of locally produced cytokines, biologically active molecules and hormones. A special balance between TH1 and TH2 lymphocytes has also been observed at the feto-maternal barrier that contribute to control the immune response at this level. An important role is played by trophoblast cells that act as a physical barrier forming a continuous layer and exert immunomodulatory function. Trophoblast cells have also been shown to express regulators of the complement system and to downregulate the expression of HLA antigens. Dysfunction of these cells leads to morphological and functional alterations of the feto-maternal barrier as well as to hormonal and immune imbalance and may contribute to the development of pathologic conditions of pregnancy, such as recurrent spontaneous abortions. Efforts are still needed to better understand the physiology of the feto-maternal interaction and the pathogenetic mechanisms responsible for tissue damage in pathologic conditions of pregnancy.