The endothelin receptor-ligand system includes a family of polypeptides and G-protein-coupled receptors, which, in addition to their classic activity in the regulation of vascular tone (both directly and through the control of nitric oxide), were implicated in a wide variety of other key biological processes. In this regard, the endothelins are potent mitogens and motogens for mesenchymal cells, and can induce cell differentiation, increasing both the synthesis and deposition of extracellular matrix components and contractile ability. The endothelins are produced as inactive pre-pro-polypeptides, with gene transcription (as well as the proteolytic processing to mature active forms) under the influence of many factors, including cytokines, hypoxia, biomechanical and shear stress, pathogen products, and many growth factors. These complex regulatory events underlie the association and potential role of endothelins in a number of human diseases affecting many different target organs, including the vasculature (atherosclerosis and hypertension), kidney (renal crisis and chronic kidney disease), heart (coronary heart disease), and lungs (pulmonary fibrosis and pulmonary hypertension). This review focuses on the biochemistry of endothelin and the pathobiology of endothelin in lung fibrosis, with particular emphasis on idiopathic pulmonary fibrosis, and examines the antifibrotic potential of endothelin receptor antagonism.