<p>During early embryonic development in mammals, the totipotency of the zygote — which is reprogrammed from the differentiated gametes — transitions to pluripotency by the blastocyst stage, coincident with the first cell fate decision. These changes in cellular potency are accompanied by large-scale alterations in the nucleus, including major transcriptional, epigenetic and architectural remodelling, and the establishment of the DNA replication programme. Advances in low-input genomics and loss-of-function methodologies tailored to the pre-implantation embryo now enable these processes to be studied at an unprecedented level of molecular detail in vivo. Such studies have provided new insights into the genome-wide landscape of epigenetic reprogramming and chromatin dynamics during this fundamental period of pre-implantation development.</p>