The incidence of chronic kidney disease (CKD) is increasing worldwide. Cardiovascular disease is strongly associated with CKD and constitutes one of its major causes of morbidity and mortality. Although current treatments for CKD focus on blood pressure and proteinuria reduction, many CKD patients have ongoing hypertension and residual proteinuria. Newer treatments are needed that not only act on these parameters, but also slow the progression of CKD and improve the cardiovascular risk profile of CKD patients. The endothelins (ETs) are a family of related peptides of which ET-1 is the most powerful endogenous vasoconstrictor and the predominant isoform in the cardiovascular and renal systems. The ET system has been widely implicated in both cardiovascular disease and CKD. ET-1 contributes to the pathogenesis and maintenance of hypertension and arterial stiffness, as well endothelial dysfunction and atherosclerosis. By reversal of these effects, ET antagonists may reduce cardiovascular risk. In CKD patients, antagonism of the ET system may be of benefit in improving renal hemodynamics and reducing proteinuria. ET is likely also involved in the progression of renal disease, and data are emerging that suggest a synergistic role for ET receptor antagonists with angiotensin-converting enzyme inhibitors in slowing CKD progression.