In recent years, it was shown that the Endothelin (ET)- and Nitric Oxide (NO)- Systems are both paracrine hormonal systems that are part of a local, tightly adjusted network1. In pulmonary and systemic hypertension, coronary artery disease and congestive heart failure, the ratio between ET-1 and NO production, more than the absolute concentration of both of them is disturbed. In mammalians, there are two ET receptors described: ETA and ETB. ET-1 induced ETB activation stimulates the endothelial nitric oxide synthase (eNOS) in endothelial cells. Thus both systems are tightly connected and control each other. I will review the preclinical and clinical implications of the interaction of both systems in health and disease status.