Molecules with immunological functions abound in hemochorial mammalian placentas where maternal blood and tissues are in direct contact with fetal placental cells. For the most part, investigators have focused on the possibility that these molecules are primarily in place for the purpose of preventing maternal immune mechanisms from attacking the genetically different fetal cells. Yet information collected in recent years indicates that these immunological mediators may serve other, non-immunological functions in placentas. In this article we discuss two families of these molecules investigated in our and other laboratories, namely the tumor necrosis factor superfamily (TNFSF) and the human leukocyte antigen (HLA) family, and present accumulating evidence for dichotomy of function during gestation.