We found that endothelin-1 causes hypertension in mice and humans by modifying macrophage number and their phenotype. Mouse macrophages and human monocytes express both ETA and ETB receptors, and show chemokinesis to endothelin-1. These immune cells then remove endothelin through ETB receptor-mediated endocytosis. Macrophage depletion amplifies the acute and chronic hypertensive response to ET-1. Mice with myeloid cell-specific ETB receptor deletion displayed an exaggerated hypertensive response to ET-1 and angiotensin II. In patients who received Mφ-depleting immunotherapy, blood pressure was higher and endothelial function worse than in those receiving non-depleting therapies. Overall, macrophages appear to play an important role in blood pressure control and potentially have a critical role as a therapeutic target in hypertension.