The progression of chronic renal failure follows a stereotypical course. Regardless of the type of underlying disease, there is a continuous loss of renal function reflected by a decline in the glomerular filtration rate and a hyperbolic increase in serum creatinine levels. This decline in renal function results from progressive nephron loss. When studied histologically, the degeneration of the kidney follows a pattern known as' classic'focal segmental glomerulosclerosis (FSGS) with tubulointerstitial fibrosis. No generally accepted concept has so far been advanced to explain this uniform process of FSGS development. We have studied this process in several animal models [1-8], and propose a mechanism crucially based on destruction of the complex glomerular tuft architecture (architectural lesions') up to a point at which repair is no longer possible. In this process, podocytes play the dominant role.