Anchoring villi are peripheral trophoblastic specializations that attach the placenta to the uterine wall. In addition, they supply the migratory trophoblast population that colonizes the maternal interstitium and arteries during the first 18 weeks of pregnancy. Establishment of anchoring villi and subsequent invasion of maternal uterine stroma and blood vessels play a critical role in pregnancy success; incomplete vascular invasion is associated with common pathological conditions of pregnancy, including spontaneous abortion, pre-eclampsia and growth retardation. Anchoring villi are already present as early as 18 days after ovulation, but new villi develop rapidly as the placenta grows. First trimester mesenchymal floating villi, when confronted with a permissive extracellular matrix (ECM) in explant culture, undergo de novo development of anchoring sites. The cellular and molecular characteristics of these specializations closely resemble those that are seen in vivo. It is postulated that development of new sites is important in the stabilization of placental attachment during growth and development in the first trimester. This may be compromised by function-blocking antibodies which inhibit cell-ECM interactions. This is supported by experiments in vitro as well as by the presence of auto-antibodies to adhesion molecules in women suffering from recurrent spontaneous miscarriage.