During mouse preimplantation development, the SOX2+ inner cell mass (ICM) forms from the interior cells of the morula, whereas CDX2+ trophectoderm (TE) differentiates from peripheral cells. Subsequently, the ICM differentiates into the primitive endoderm (PrE) and epiblast (EPI). The extrinsic mechanisms that instruct ICM specification and patterning, however, are not fully understood. Now, Takashi Hiiragi and colleagues investigate the role of the extracellular matrix (ECM) in ICM specification. Using immunohistochemistry, the authors show enrichment of ECM components (such as laminin-511) and reciprocal receptors (such as integrin β1) at cell-cell contacts within the morula. Culturing embryos without TE reveals that ICM cells directly exposed to culture media upregulate CDX2, thereby restoring TE/ICM patterning. When cultured on Matrigel, however, the TE is not restored and ICM specification increases as cells divide, unless integrin β1 is ablated. Similar results are seen in EPI/PrE organisation, with the expression pattern of GATA4 (PrE) and SOX2 (EPI) reversed when cultured on Matrigel versus media in an integrin β1-dependent manner. In vivo, loss of integrin β1 or laminin γ1 (a component of laminin-511) results in defective blastocyst cell morphology and organisation. Together, these data reveal that laminin-integrin interactions provide positional cues for ICM patterning.