Mutation of the mouse laminin 5 gene results in a variety of developmental defects, including defects in kidney structure and function. Whereas the total absence of laminin α5 results in breakdown of the glomerular basement membrane (GBM) and failed glomerular vascularization, a hypomorphic Lama5 mutation (the Lama5neo allele) results in proteinuria, hematuria, polycystic kidney disease (PKD), and death 3 to 4 weeks after birth. Here, we examined the role of podocyte-derived laminin α5 via podocyte-specific inactivation of Lama5 and podocyte-specific rescue of the Lama5neo mutation. Podocyte-specific inactivation of Lama5 resulted in varying degrees of proteinuria and rates of progression to nephrotic syndrome. The GBM of proteinuric mice appeared thickened and "moth-eaten," and podocyte foot processes became effaced. Podocyte-specific restoration of laminin α5 production using two distinct strategies in Lama5neo/neo mice resulted in the resolution of proteinuria, hematuria, and PKD. These results suggest that the development of normal GBM structure and function requires podocytederived laminin α5 during and after glomerulogenesis and present a unique mechanism for the pathogenesis of PKD in these mice.