Excessive sodium reabsorption by the kidney has long been known to participate in the pathogenesis of some forms of hypertension. In the kidney, the final control of NaCl reabsorption takes place in the distal nephron through the amiloride-sensitive epithelial sodium channel (ENaC). Liddle's syndrome, an inherited form of hypertension due to gain-of-function mutations in the genes coding for ENaC subunits, has demonstrated the key role of this channel in the sodium balance. Although aldosterone is classically thought to be the main hormone regulating ENaC activity, several studies in animal models and in humans highlight the important effect of vasopressin on ENaC regulation and sodium transport. This review summarizes the effect of vasopressin V2 receptor stimulation on ENaC activity and sodium excretion in vivo. Moreover, we report the experimental and clinical data demonstrating the role of renal ENaC in water conservation at the expense of a reduced ability to excrete sodium. Acute administration of the selective V2 receptor agonist dDAVP not only increases urine osmolality and reduces urine flow rate but also reduces sodium excretion in rats and humans. Chronic V2 receptor stimulation increases blood pressure in rats, and a significant correlation was found between blood pressure and urine concentration in healthy humans. This led us to discuss how excessive vasopressin-dependent ENaC stimulation could be a risk factor for sodium retention and resulting increase in blood pressure.