The placenta provides critical transport functions between the maternal and fetal circulations during intrauterine development. Formation of this interface relies on coordinated interactions among transcriptional, epigenetic, and environmental factors. Here we describe these mechanisms in the context of the differentiation of placental cells (trophoblasts) and synthesize current knowledge about how they interact to generate a functional placenta. Developing an understanding of these pathways contributes to an improvement of our models for studying trophoblast biology and sheds light on the etiology of pregnancy complications and the in utero programming of adult diseases.