Transforming growth factor-beta (TGF-beta) isoforms are multifunctional cytokines that play a central role in wound healing and in tissue repair. TGF-beta is found in all tissues, but is particularly abundant in bone, lung, kidney and placental tissue. TGF-beta is produced by many but not all parenchymal cell types, and is also produced or released by infiltrating cells such as lymphocytes, monocytes/macrophages, and platelets. Following wounding or inflammation, all these cells are potential sources of TGF-beta. In general, the release and activation of TGF-beta stimulates the production of various extracellular matrix proteins and inhibits the degradation of these matrix proteins, although exceptions to these principles abound. These actions of TGF-beta contribute to tissue repair, which under ideal circumstances leads to the restoration of normal tissue architecture and may involve a component of tissue fibrosis. In many diseases, excessive TGF-beta contributes to a pathologic excess of tissue fibrosis that compromises normal organ function, a topic that has been the subject of numerous reviews [1-3]. In the following chapter, we will discuss the role of TGF-beta in tissue fibrosis, with particular emphasis on renal fibrosis.