Endothelin-1 (ET-1) is a potent vasoconstrictor. It induces vascular contraction, stimulates proliferation of vascular smooth muscle cells and vascular remodeling in the pathogenesis of cardiovascular disease including pulmonary hypertension. Many studies have demonstrated that activation of mitogen-activated protein kinase (MAPK)/nuclear factor-kappaB (NF-κB) signal pathway induces up-regulation of endothelin receptors, and the up-regulation of endothelin receptors in pulmonary vascular smooth muscle cells results in pulmonary artery hypersensitivity and hyperresponsiveness to ET-1 with enhanced pulmonary vascular contraction, even spasm. This review article summarizes the roles of endothelin-1 and its receptors in the pathogenesis of pulmonary hypertension with focusing on the relationships between the up-regulation of endothelin receptors and pulmonary hypersensitivity and hyperresponsiveness, as well as down-regulation of endothelin receptors by inhibiting MAPK/NF-κB signal pathway. The inhibition of the endothelin receptor up-regulation in pulmonary artery improves pulmonary hypersensitivity and hyperresponsiveness to ET-1, and thus may provide a new strategy and novel therapeutic targets for the treatment of pulmonary hypertension.