The amiloride-sensitive epithelial sodium channel (ENaC) constitutes the rate-limiting step for sodium reabsorption in epithelial cells that line the distal part of the renal tubule, the distal colon, the duct of several exocrine glands, and the lung. The activity of this channel is regulated by aldosterone and hormones involved in the maintenance of sodium balance, blood volume and blood pressure. In this review, we discuss recent advances in our understanding of ENaC function and regulation relevant to the control of sodium balance and blood pressure. The identification of novel drug targets should help in the development of the next generation of diuretics and of new therapies for the treatment of hypertension.