Embryo implantation and placentation are essential for the establishment of pregnancy. Abnormalities in implantation and placentation can result in pregnancy complications including miscarriage, intrauterine growth restriction and preeclampsia. The embryo attaches and invades into an adequately prepared or receptive endometrium. The embryonic extravillous trophoblast (EVT) must adhere to and invade through an adequately prepared or receptive endometrium to tap into the maternal blood supply and form a functional placenta. Decidualization or differentiation of human endometrial stromal cells (HESC) is initiated in the mid-secretory (receptive) phase of the menstrual cycle and if implantation occurs decidualization progresses to form the decidua of pregnancy. Studies in mice have demonstrated that abnormal decidualization of endometrial stromal cells leads to unregulated trophoblast invasion and pregnancy failure. Recent evidence in humans suggests that preeclampsia is associated with impaired decidualization. Very few studies have investigated whether adequate decidualization is important in regulating the EVT invasion in humans. Our recent studies demonstrated that EVT adhesion and invasion to HESC is differentially altered in relation to the extent of HESC decidualization. Using a proteomics approach we demonstrated that decidualized and non-decasualized HESC altered unique cohorts of trophoblast membrane and secreted proteins. Non-decidualized HESC primarily stimulated pro-inflammatory molecules in EVT. Our studies demonstrated that the extent of decidualization is critical for EVT function and that the decidua is not passive to EVT invasion - EVTs respond to paracrine cues from decidual cells. Our studies suggest that adequate decidualization is required to facilitate appropriate EVT invasion. We propose that women with defective decidualization in the mid-secretory phase of the menstrual cycle may be susceptible to developing conditions associated with placental insufficiency.