Endothelin-1 is a potent regulator of vasomotor tone and promotes endothelium-dependent vasoconstriction of vascular smooth muscle. Dysregulated vasomotor tone is a hallmark of microvascular pathology following cardiac surgery involving cardioplegia and cardiopulmonary bypass (CPB). This review begins with a discussion of the molecular biology of endothelin-1, the structure and function of endothelin receptors, and an overview of endothelin signaling pathways and endogenous regulation. Following this, the focus will turn to an exploration of abnormal endothelin-1 activity during and after CPB across different vascular systems, including coronary, pulmonary, skeletal muscle, peripheral, and mesenteric circulation. Finally, this review concludes with a discussion of drugs targeting endothelin-1 signaling pathways to protect vasomotor tone and microvascular function from ischemia/reperfusion-induced damage, highlighting new therapeutic targets to reduce postoperative morbidity and mortality.