Endothelin has emerged as a target for therapeutic intervention in systemic hypertension. As a vasoconstrictor, comitogenic agent, linking pulse pressure and vascular remodeling, and mediator of aldosterone and catecholamine release, endothelin is a key player in hypertension and end-organ damage. In 10%-20% of the hypertensive population, the high blood pressure is resistant to administration of antihypertensive drugs of different classes in combination. Because endothelin is not targeted by the current antihypertensive drugs, this may suggest that this resistance is due, in part at least, to a dependence on endothelin. This hypothesis is supported by the observation that this form of hypertension is often salt-sensitive, and that the endothelin system is stimulated by salt. In addition, the endothelin system is activated in subjects at risk of developing resistant hypertension, such as African Americans or patients with obesity or obstructive sleep apnea. Aprocitentan is an investigational, novel, potent, dual endothelin receptor antagonist (ERA) currently in phase 3 development for the treatment of difficult-to-treat hypertension. This article discusses the research that underpinned the discovery of this ERA and the choice of its first clinical indication for patients with forms of hypertension that cannot be well controlled with classical antihypertensive drugs.