The stereotyped development of the glomerular lesions in many animal models and human forms of progressive renal disease suggests that there are common mechanisms of disease progression. We propose the outline of such a mechanism based on following aspects: (1) The glomerulus is a complex structure, the stability of which depends on the cooperative function of the basement membrane, mesangial cells and podocytes, counteracting the distending forces originating from the high glomerular hydrostatic pressures. Failure of this system leads to quite uniform architectural lesions. (2) There is strong evidence that the podocyte is incapable of regenerative replication post-natally; when podocytes are lost for any reason they cannot be replaced by new cells. Loss of podocytes may therefore lead to areas of "bare" GBM. which represent potential starting points for irreversible glomerular injury. (3) Attachment of parietal epithelial cells to bare GBM invariably occurs when bare GBM coexists with architectural lesions, leading to the formation of a tuft adhesion to Bowman's capsule, the first "committed" lesion progressing to segmental sclerosis. (4) Within an adhesion the tuft merges with the interstitium, allowing filtration from perfused capillaries inside the adhesion towards the interstitium. The relevance of such filtration is as yet unclear but may play a considerable role in progression to global sclerosis and interstitial fibrosis.