During early pregnancy, fetal chorionic villi that contact the uterine wall give rise to columns of mononuclear cytotrophoblasts that penetrate the superficial portion of the uterus. From these columns emanate cytotrophoblasts that invade deeply into the uterus and its arterioles. To investigate the molecular basis of this unusual, regulated invasive behavior, we used a combination of approaches that included an in vitro model of cytotrophoblast invasion and immunocytochemistry on uterine biopsy sections containing invading cytotrophoblasts. Our results showed interesting roles for: matrix-degrading metalloproteinases, adhesion receptors and their extracellular matrix ligands, and the class I molecule HLA-G.