During the early stages of mammalian development, the epigenetic state of the parental genome is completely reprogrammed to give rise to the totipotent embryo. An important aspect of this remodeling concerns the heterochromatin and the spatial organization of the genome. While heterochromatin and genome organization are intricately linked in pluripotent and somatic systems, little is known about their relationship in the totipotent embryo. In this review, we summarize the current knowledge on the reprogramming of both regulatory layers. In addition, we discuss available evidence on their relationship and put this in the context of findings in other systems