Renal fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common pathway of a wide variety of chronic kidney diseases (CKD). Regardless of the underlying disorder and whether the injury is sustained, the kidney will follow a doomsday path of fibrogenesis, a condition characterized by excessive extracellular matrix accumulation. Can we do anything to slow the rate of functional decline associated with fibrotic renal diseases? This major challenge requires an understanding of the mechanisms involved in the pathogenesis of renal fibrosis. Doing so may allow us to develop new therapeutic targets to ameliorate disease directly and to identify those who are at risk for future disease. It should be stressed that renal fibrosis is a dynamic process in which many cellular events occur simultaneously, often in a mutually stimulating manner. These events include increased matrix production, inhibition of matrix degradation, modulation of matrix receptors to facilitate cell–matrix interactions, mesangial and fibroblast activation, tubular epithelial-to-mesenchymal transition, monocytic and lymphocytic cell infiltration, and cell apoptosis. It is also widely accepted that TGF-β and its downstream Smad signaling play an essential role in tissue fibrosis in general and in renal fibrosis in particular. Therefore, therapeutic targeting of TGF-β is seemingly critical and attractive and holds much hope for slowing or halting fibrosis. Attempts to block renal fibrosis have been successful in laboratory settings but have fallen short of the goal in clinical practice. The approach of limiting fibrosis through angiotensin II inhibition or antagonism has been exploited clinically, but the success has been limited. In the laboratory setting, some of the TGF-β–targeted therapies have included neutralizing antibodies, antisense oligonucleotides, …