Injury of the glomerular microvasculature by nonimmunologic processes is often the underlying mechanism of progressive deterioration of renal function in patients with a variety of renal disorders. The structural hallmark of this injury is focal and segmental glomerulosclerosis, often accompanied by entrapment of hyalin. Although such lesions are quite characteristic for diseases that primarily affect the glomerular podocyte, similar damage occurs in association with functional and structural adaptive changes that develop as a consequence of a significant loss of functioning nephrons or other systemic disorders. Experimental studies have revealed that such functional adaptations include intrarenal vasodilatation that through increases in glomerular capillary pressure and plasma flow leads to a significant compensatory hyperfiltration. This functional state is accompanied by a parallel increase in glomerular volume, attained chiefly by expansion of matrix components and an increase in the number of endothelial and mesangial cells, but not of podocytes. The persistence of the adaptive changes results in endothelial, mesangial, and epithelial cell dysfunction revealed clinically by proteinuria and structurally by the development of microthrombosis, microaneurysms, mesangial expansion, and occlusion of capillaries by hyalin accumulation. Although all these pathologic processes can lead to segmental collapse of the capillary tuft, it is the progressive hyalin deposition in capillaries with defective or detached podocytes that represents the major mechanism in the development of segmental and eventually global glomerulosclerosis. The inability of the highly differentiated podocyte to replicate in response to systemic or locally released trophic factors ultimately results in imperfections of the capillary wall that set the stage for permeability defects amplified and accentuated by greatly augmented hydrodynamic forces. These structural and functional microvascular changes acting in concert not only facilitate the transcapillary convection of macromolecules that results in albuminuria, but can also be anticipated to play a key role in the entrapment and accumulation of larger macromolecules in front of the lamina densa in the form of hyalin material. Continuing damage to the glomerular microvasculature exacerbates the adaptive changes in surviving nephrons, closing a positive-feedback loop that culminates in end-stage renal failure.