Endothelin-1 (ET-1) regulates renal salt and water excretion and arterial pressure (BP). The collecting duct (CD) is particularly important; it produces and binds more ET-1 than any other region of the kidney. CD-specific knockout (KO) of the ET-1 system indicates that CD-derived ET-1 modulates Na homeostasis and BP. CD-specific KO of ET-1 causes salt-sensitive hypertension and Na retention as well as impaired excretion of a water load due to enhanced sensitivity to vasopressin-stimulated cAMP accumulation. CD-specific ETA receptor KO mice do not have altered BP or Na excretion. CD-specific ETB receptor KO mice exhibit salt-sensitive hypertension, albeit less severe that in ET-1 deficient animals. Surprisingly, CD KO of both ETA and ETB receptors causes hypertension and Na retention almost identical to CD ET-1 KO mice, suggesting an interaction between ETA and ETB receptors. Patch clamp of the apical membrane of acutely isolated mouse cortical CDs reveals that exogenous and endogenous ET-1 reduces epithelial Na channel open probability through ETB receptor activation of src and MAPK. Studies in CD ET-1 KO mice indicate that nitric oxide also mediates ET-1 effects on Na excretion and BP. Salt loading increases urinary ET-1 excretion and renal medullary ET-1 content, suggesting that CD ET-1 production is stimulated by volume expansion. Initial studies show that increased tubular fluid flow, as occurs in volume expansion, augments CD ET-1 synthesis. Flow increases CD intracellular calcium concentration that, via calmodulin and calmodulin kinase II, increases ET-1 gene transcription through NFAT consensus sequences in a CD-specific region of the ET-1 promoter. Finally, CD-derived ET-1 may play a role in the pathogenesis of hypertension since renal medullary ET-1 content is reduced in experimental hypertension, while urinary ET-1 excretion is often decreased in human essential hypertension. In summary, CD-derived ET-1 is an important regulator of renal Na excretion and BP under physiologic and pathophysiologic conditions.