During pregnancy, interactions between maternal immune cells and fetal trophoblast cells of the placenta would seemingly lead to disaster, as the trophoblast cells are semi-allogeneic and should trigger rejection by the maternal immune response. A fundamental immunologic question of pregnancy as posed by Sir Peter Medawar centers on how immunologic disaster is averted. It is becoming clear that many different mechanisms act during gestation to render the maternal immune system tolerant of the fetus. These include, among others, restricted major histocompatibility complex (MHC) protein expression, the presence of immunosuppressive B7 family members, immunomodulatory adhesion molecules, the expression of apoptosis-inducing proteins, and complement regulatory proteins. Understanding of maternal-fetal tolerance has clinically important implications for the fields of reproduction, autoimmunity and transplantation. Herein are discussed mechanisms by which trophoblast cells are protected from maternal immune cell attack. Specifically the role of trophoblast cell surface proteins at the maternal-fetal interface is considered.