Renal fibrosis is the common end point of virtually all progressive kidney diseases. Renal fibrosis should not be viewed as a simple and uniform 'scar', but rather as a dynamic system that involves extracellular matrix components and many, if not all, renal and infiltrating cell types. The involved cells exhibit enormous plasticity or phenotypic variability-a fact that we are only beginning to appreciate. Only a detailed understanding of the underlying mechanisms of renal fibrosis can facilitate the development of effective treatments. In this Review, we discuss the most recent advances in renal, or more specifically, tubulointerstitial fibrosis. Novel mechanisms as well as potential treatment targets based on different cell types are described. Problems that continue to plague the field are also discussed, including specific therapeutic targeting of the kidney, the development of improved diagnostic methods to assess renal fibrosis and the shortcomings of available animal models.