Early pregnancy loss in humans, which often occurs due to defects that occur before, during or immediately after implantation, is a worldwide social and economic concern. For successful implantation to occur in the receptive uterus, the blastocyst must also attain implantation competency. The first evidence that the state of activity of the blastocyst determines the “window” of implantation in the receptive uterus was derived from reciprocal blastocyst transfer experiments in a delayed implantation mouse model. This model is a powerful approach to define the molecular signaling components that direct blastocyst activation or dormancy. Nearly 100 mammals in seven different orders undergo delayed implantation, but the underlying mechanism remains largely unknown. There is evidence that catecholestrogens produced from primary estrogens in the uterus activate blastocysts. Another lipid signaling molecule that targets blastocysts is an endocannabinoid anandamide, which activates G-protein coupled cannabinoid receptors CB1 and CB2. Expression of CB1 in the Tr, and uterine synthesis of anandamide, suggest that endocannabinoid signaling is critical to implantation in mice. Levels of uterine anandamide and blastocyst CB1 are coordinately downregulated with the attainment of uterine receptivity and blastocyst activation, respectively, in contrast to their elevated levels in the nonreceptive uterus and dormant blastocysts. Anandamide regulates blastocyst function by differentially modulating MAPK signaling and Ca2+channelactivityviaCB1. Using delayed implantation model, a global gene expression study showed that these two different physiological states of the blastocyst are molecularly distinguishable. The main functional categories of altered genes include cell cycle, cell signaling and energy metabolic pathways. This study also showed an upregulated expression of heparin-binding EGF-like growth factor (HB-EGF) in activated blastocysts and is complementary to earlier reports of upregulated expression of its receptor ErbB1 and ErbB4 in similar blastocysts. Recently, we demonstrated that silencing of Wnt-beta-catenin signaling in mice does not adversely affect the development of preimplantation embryos to blastocysts and uterine preparation for receptivity, but, remarkably, blocks blastocyst competency to implantation. A coordinated activation of canonical Wnt-beta-catenin signaling with Cox-2-PPARd signaling pathway ensures blastocyst competency to implantation. These findings constitute novel evidence that Wnt signaling is at least one pathway that determines blastocyst competency for implantation. More insight into the molecular basis of blastocyst competency for implantation might help to improve pregnancy rates in human IVF programs.