Fibroblasts are one of the most important and episodically active cell types in the kidney. Under normal conditions, these cells provide a delicate collagenous matrix that partitions the interstitial spaces between nephrons, blood vessels and the renal capsule. Fibroblasts also remodel the interstitium as kidneys grow with age. This episodic activity of various fibroblast populations has a biological basis. Most fibroblasts are created locally through a process called epithelial–mesenchymal transition (EMT) and, once formed, they can proliferate in response to local mitogens. EMT is driven by an alteration in the balance of local cytokine concentrations that reverses the differentiation of selected epithelia along tubular nephrons. During persistent injury and inflammation, fibroblasts further increase their numbers and secrete excess interstitial collagens, and EMT is particularly aggressive in this setting. The mechanisms by which fibroblasts simultaneously destroy normal interstitial architecture and disable epithelial nephrons are more comprehensible today. Recent therapeutic clues for attenuating fibroblast formation during renal fibrogenesis also suggest an advantage in shifting local cytokine balance to favor mesenchymal–epithelial transition. This review examines these issues and identifies new targets for the treatment of one of the most difficult problems facing clinical nephrology.