Most human pregnancies fail around the time of embryo implantation. Yet, the developmental mechanisms of this stage and how they go awry remain a mystery, because the implanted embryo is inaccessible to analysis within the body of the mother. Uncovering these mechanisms is of critical importance to overcome existing barriers to fertility and proper development. We have successfully generated systems that enable development of natural mouse and human embryos from pre- to post-implantation stages in vitro, and built stem cell-derived synthetic mouse embryos that can mimic some aspects of early post-implantation development. But approaches to study development continuously through the implantation stage and beyond gastrulation are lacking. We now propose to create a maternal-like environment that permits the long-term survival of both natural and synthetic mouse embryos. Our first challenge will be to engineer synthetic pre-implantation blastocysts with an expanded ability to generate the full range of correctly functioning extra-embryonic tissues. This breakthrough is expected to enable their implantation and development in utero, and may eventually transform approaches for engineering genetically modified mice. We will use these new tools to determine the precise cellular and molecular mechanisms that allow synthetic blastocysts to interact with the uterus in foster mothers. Our second challenge will be to generate artificial substrates, comprising hydrogels and proteins of the decidual extra-cellular matrix, to facilitate implantation events. In parallel, we will engineer synthetic placental-like structures for natural and synthetic embryo development using organoids derived from trophoblast and endometrial tissue. These systems would allow investigations and tracking of how insults to pre- and peri-implantation development, such as the exposure to pathogens, toxins, or teratogens affect subsequent development and life. Our third challenge will be to utilize these systems to discover the molecular events that accompany implantation. We will take advantage of our in vitro placental systems to investigate the chemical and physical signalling events that are key for development and determine how improved extra-embryonic contributions affect embryonic development until neurulation. These innovations will allow us to finally decipher a stage of development that is currently out of reach and of which our knowledge is greatly lacking. This will bring insight into a time of development when most pregnancies fail and thereby lead to advances in assisted reproductive technology; it will offer new screening routes for drug testing and environmental safety; and it will advance our knowledge of the use of stem cells in organogenesis and regenerative medicine.