The nephrotic syndrome represents a series of physiological results ensuing from the occurrence of significant urinary loss of protein. Although the common initiating event of proteinuria has long been established, the list of problems that result has continued to grow as our understanding of the pathophysiology of nephrosis has increased. This article discusses this pathophysiology, emphasizing the consequences of nephrotic-range proteinuria. These consequences include not only acute and subacute manifestations of disrupted homeostasis, but also ways in which nephrosis itself may amplify mechanisms by which progressive renal nephron loss occurs. New insights into the factors that initiate and maintain glomerulosclerosis and interstitial fibrosis may offer potential approaches to preventing or ameliorating chronic renal insufficiency.