During blastocyst development, asymmetric cell divisions generate polar and apolar daughter cells, which organise into outer and inner positions, respectively, to form the trophectoderm (TE) and inner cell mass (ICM) lineages. The Hippo signaling pathway is crucial for setting up this early lineage specification, but how Hippo signaling relates to cell position and polarity remains unclear. In this issue (p. 2813), Yojiro Yamanaka and colleagues carefully analyze the initiation process of the first lineage specifications in the 16-cell mouse embryo. The authors count the number of polar/apolar cells and outer/inner cells in intact embryos and find that many apolar cells are located in outer positions with only one or two cells fully internalized. Notably, many of these outer apolar cells have high cytoplasmic phosphorylated YAP, an early marker for inner cells. Further analysis of isolated 8-cell blastomeres confirms that polar and apolar cells have intrinsic differences in the regulation of phosphorylated YAP prior to setting up the outer/inner configurations in the embryo. The authors suggest that polarity regulates the outer/inner cell positioning, as well as Hippo signaling, in order to activate TE and ICM lineage specification.