Laminins are heterotrimeric glycoproteins of the basement membranes. Laminin 1 (α1, β1, γ1) is the major laminin expressed during early mouse embryogenesis. To gain access to the physiological function of laminin α1 chain, we developed a conditionally null allele of its encoding gene (Lama1) using the cre/loxP system. Floxed‐allele‐carrying mice (Lama1^flox/flox) display no overt phenotype. Lama1^flox/flox mice were crossed with transgenic deleter mice (CMV‐Cre) to generate Lama1‐deficient mice (Lama1^Δ/Δ). Lama1^Δ/Δ embryos die during the early postimplantation period after embryonic day 6.5. They lack Reichert's membrane, an extraembryonic basement membrane in which laminin α1 is normally highly expressed. In parallel, Lama1^Δ/Δ embryos display 1) parietal and visceral endoderm differentiation defects with altered expression of cytokeratin 19 and GATA4, respectively, and 2) an induction of apoptosis. This new mouse model is of particular interest as it will allow time‐ and tissue‐specific inactivation of the Lama1 gene in various organs. genesis 43:59–70, 2005. © 2005 Wiley‐Liss, Inc.