Abstract
Our understanding of how the first mammalian cell lineages arise has been shaped largely by studies of the preimplantation mouse embryo. Painstaking work over many decades has begun to reveal how a single totipotent cell is transformed into a multilayered structure representing the foundations of the body plan. Here, we review how the first lineage decision is initiated by epigenetic regulation but consolidated by the integration of morphological features and transcription factor activity. The establishment of pluripotent and multipotent stem cell lines has enabled deeper analysis of molecular and epigenetic regulation of cell fate decisions. The capability to assemble these stem cells into artificial embryos is an exciting new avenue of research that offers a long-awaited window into cell fate specification in the human embryo. Together, these approaches are poised to profoundly increase our understanding of how the first lineage decisions are made during mammalian embryonic development.