The incidence and prevalence of chronic kidney disease (CKD) is increasing. Despite current therapies, many patients with CKD have suboptimal blood pressure, ongoing proteinuria, and develop progressive renal dysfunction. Further therapeutic options therefore are required. Over the past 20 years the endothelin (ET) system has become a prime target. Experimental models have shown that ET-1, acting primarily via the endothelin-A receptor, plays an important role in the development of proteinuria, glomerular injury, fibrosis, and inflammation. Subsequent animal and early clinical studies using ET-receptor antagonists have suggested that theses therapies may slow renal disease progression primarily through blood pressure and proteinuria reduction. This review examines the current literature regarding the ET system in nondiabetic CKD.