PURPOSE OF REVIEW: In general, the nitric oxide and endothelin signaling pathways in the kidney promote natriuresis. The basis for this statement will first be reviewed for each of these systems. Next, this review will outline the progression of data providing support for our hypothesis that an intra-renal mechanism of endothelin activation of ETB receptors stimulates NOS1 activity and nitric oxide production to promote sodium excretion. RECENT FINDINGS: New information in recent years has provided considerable evidence that both nitric oxide and endothelin function to regulate sodium and water balance by the kidney. Furthermore, dysfunction of these pathways may play a role in salt-sensitivity and hypertension. While a strong picture has emerged to suggest these systems are important and powerful players in sodium homeostasis, many questions remain to be answered before we can apply these mechanisms to an understanding of clinical hypertension. SUMMARY: Salt-sensitive hypertension contributes to the growing population of patients resistant to conventional antihypertensive therapy. Thus, a thorough understanding of the mechanisms related to the control of sodium excretion will allow a more focused approach for future therapeutic studies. © 2008 Lippincott Williams & Wilkins, Inc.