Pregnancy is a distinct physiological context in which the mother hosts and nurtures the development of a genetically distinct fetus. Healthy pregnancy outcomes rely on successful placental development, during which specialized placental cells with fetal genotype, known as trophoblasts, drive the establishment of the maternal-fetal interface, a balanced tissue ecosystem that supports fetal development while safeguarding maternal well-being. Advances in single-cell, single-nuclei and spatial genomics technologies, along with data science, are now providing an unprecedented view of trophoblast regulation, which drives their differentiation into diverse cell subtypes that dynamically transform the maternal niche. More specifically, these cells modulate the immune system and remodel the vasculature to facilitate communication with maternal cells, leading to the successful formation of the maternal-fetal interface. These advances, when combined with in vitro modelling, hold promise for inferring causality in mechanisms that govern genome regulation, cellular behaviour and ultimately pregnancy homeostasis and maladaptive responses.