Cardiac fibrosis is a detrimental process that results in a progressive stiffening of the ventricular walls, loss of contractility, and abnormalities in cardiac conductance. Irrespective of the cause, cardiac fibrosis is associated with excessive buildup of extracellular matrix proteins by fibroblastic cells in the perivascular and myocardial interstitial compartments. Recent reports suggest that a significant fraction of these interstitial fibroblasts are derived from the endothelium by a transforming growth factor beta-dependent process called endothelial-to-mesenchymal transition (endo-MT). The generation of mesenchymal profibrotic cells from endothelial cells by this process appears to recapitulate the transdifferentiation of endothelial cells that leads to the formation of the cardiac valves in embryonic development. In cardiac fibrosis, endo-MT may not only contribute to the generation of profibrotic cells but also a reduction in capillary density, also termed rarefaction. Here we will review the role of transforming growth factor beta in endo-MT in embryonic development and its potential role in cardiac fibrosis. Endo-MT may well act as a profibrotic switch and represent a novel target in the prevention of tissue fibrosis.