There are strong reasons to justify the concept that proteinuria is a major risk factor for progression in clinical trials. The evidence is strongest where therapeutic intervention has been focused on established renal disease, when changes in albumin excretion rate (AER) and glomerular filtration rate (GFR) occur within a short time span. Proteinuria is also important in emerging renal disease, such as incipient diabetic nephropathy (DN), since natural history studies show that small increases in AER predict clinical nephropathy and, ultimately, a decline in GFR. However, the absence of concurrent changes in GFR in incipient DN complicates the evaluation of clinical trials in this condition. It is also not certain that the degree of coupling of changes in AER and GFR is the same during intervention as during natural history studies. The importance of proteinuria as a risk factor for progression has been strengthened by recent evidence showing that proteinuria itself causes renal damage. Traditional concepts of the damaging effects of proteinuria have focused on the glomeruli, where mesangial expansion induced by transcapillary passage of proteins has been considered to lead to a decrease in glomerular filtration surface and a decline in GFR. New evidence suggests that interaction of albumin with proximal renal tubules may not only lead to renal damage but may also be causally related to increases in AER.