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The first cell-fate decision is the process by which cells of an embryo take on distinct lineage identities for the first time, thus representing the beginning of developmental patterning. Here, we demonstrate that the molecular chaperone heat shock protein A2 (HSPA2), a member of the 70 kDa heat shock protein (HSP70) family, is asymmetrically expressed in the late 2-cell stage of mouse embryos. The knockdown ofHspa2in one of the 2-cell blastomeres prevented its progeny predominantly toward the inner cell mass (ICM) fate. In contrast, the overexpression ofHspa2in one of the two-cell blastomeres did not induce blastomeres to differentiate towards the ICM fate. Furthermore, we demonstrated that HSPA2 interacts with CARM1 and its levels correlate with ICM-associated genes and that it interacts with the CARM1. Collectively, our results identify HSPA2 as a critical early regulator of the first cell-fate decision in mammalian 2-cell embryos.