Progressive deterioration of the kidney is common to many renal diseases. The structural injuries which lead to this progressive loss of function consist of focal segmental glomerulosclerosis and tubulointerstitial fibrosis and atrophy. These processes were previously thought to be inexorable, regardless of the primary disease. However, recent observations point to the possibility of reversal of sclerosis. Mesangial matrix accumulation is the cornerstone of glomerulosclerosis and results when matrix synthesis exceeds matrix degradation. The renin-angiotensin system appears to be one central component of this process, with links to numerous mechanisms which promote matrix accumulation. Most recently, direct induction of plasminogen activator inhibitor-1 by angiotensin has been recognized. Plasminogen activator inhibitor-1 not only promotes thrombosis, but also inhibits matrix degradation. The various mechanisms which modulate mesangial matrix accumulation and their potential reversibility are reviewed.