Collagen IV is a major structural component of all basal laminae (BLs). Six collagen IV α chains are present in mammals; α1 and α2(IV) are broadly expressed in embryos and adults, whereas α3-6(IV) are restricted to a defined subset of BLs. In the glomerular BL of the kidney, the α1 and α2(IV) chains are replaced by the α3-5(IV) chains as development proceeds. In humans, mutation of the collagen α3, α4, or α5(IV) chain genes results in a delayed onset renal disease called Alport syndrome. We show here that mice lacking collagen α3(IV) display a renal phenotype strikingly similar to Alport syndrome: decreased glomerular filtration (leading to uremia), compromised glomerular integrity (leading to proteinuria), structural changes in glomerular BL, and glomerulonephritis. Interestingly, numerous changes in the molecular composition of glomerular BL precede the onset of renal dysfunction: these include loss of collagens α4 and α5(IV), retention of collagen α1/2(IV), appearance of fibronectin and collagen VI, and increased levels of perlecan. We suggest that these alterations contribute, along with loss of collagen IV isoforms per se, to renal pathology.