Chronic renal failure (CRF) is characterized histologically by progressive glomerulosclerosis (GS) and tubulo-interstitial scarring (TIS). Recently, research has focused on the study of the pathophysiology of GS. Most advances in this field have been derived from the study of various experimental models of CRF and GS in the rat. In this paper, I will review some of the concepts and hypotheses put forward to explain progressive GS and examine their relevance to glomerular scarring and CRF in humans.