Epigenetic modifications act in combination to provide essential developmental and regulatory codes. Although maintained as predominantly static and robust patterns within healthy adult tissues, these modifications are globally reprogrammed at fertilization and must be systematically redeployed to support embryonic differentiation and growth. I will present our lab’s ongoing efforts to understand distinct forms of genome regulation as they emerge during this highly dynamic period. In particular, we hope to identify molecular pathways that distinguish the fetal epigenome from a second, seemingly more dynamic program specific to the extraembryonic placenta and yolk sac. Further insights from patient data suggest that this alternative regulatory mechanism may also be coopted as a general feature of malignant transformation in cancer. Finally, I will highlight our work to pinpoint how epigenetic complexes themselves guide the differentiating embryo through the highly coordinated processes of gastrulation and early organogenesis. We hope to ultimately integrate our observations from developmental and genome biology as a means of uncovering the environmental and epigenetic origins of complex congenital disorders.