This chapter discusses the role of the uterine immune system in the regulation of trophoblast transformation of spiral arteries. The health of both the fetus and the mother is contingent upon regulating the extent of trophoblast invasion. The placental genome has the potential to express paternal antigens and thus could potentially be recognized as non-self by the maternal immune system. The lack of highly polymorphic HLA-A and -B molecules preclude strong anti-HLA class I T cell alloreactions that could damage fetal trophoblast. The uNK cells express surface killer immunoglobulin receptors (KIR), which are known to bind to HLA-C and HLA-G on trophoblast. HLA-C+trophoblast cells intermingle with KIR+uNK cells at the site of placentation where extravillous trophoblast (EVT) transform the uterine arteries. Although variations in the extent of trophoblast invasion are influenced by multiple biological processes, the KIR-HLAC axis is still the only known polymorphic interaction between maternal and fetal cells.