If it is true that the decline in the use of available diuretics for the treatment of hypertension may in some way be related to the perception that metabolic effects may decrease their proved outcome benefits, then other metabolically neutral agents may be better choices. There may be a reason for developing other diuretics in the future. In addition to the fact that sodium-reabsorbing sites in the nephron, with potentially better patterns of electrolyte handling, may lead to better diuretic therapy, recent identification of rare mutations that affect both renal ion handling and BP provide new insights into the molecular mechanisms underlying the hypertensive trait.43 Therefore, in Gitelman syndrome, absence of the gene coding for the thiazide-sensitive sodium chloride cotransporter leads to absence of the cotransporter in the distal collecting duct in the kidneys.44 Cloning of this transporter provides an opportunity to develop highly specific diuretics, possibly nonthiazides, that would be devoid of metabolic adverse effects on lipids and glucose levels as well as the rare sulfonamide-related allergic reactions. In Bartter syndrome types 1, 2, and 3, deficits of the sodium-potassium-chloride cotransporter, the K+ channel ROMK, and the chloride channel CLCNKB, respectively,43,45 suggest that selective antagonists of these transporters and channels could be developed, with more potent diuretic potential and without the risk of hypokalemia. The hypertension observed in Liddle syndrome, in which there is overexpression of the epithelial sodium channel ENaC,46 as well as the converse, pseudohypoaldosteronism type 1, in which a deficit in ENaC is present, points toward possibilities for the development of selective antagonists that could be potassium sparing and more potent than the current ENaC inhibitor amiloride. Our increased understanding of the transport mechanisms in the kidneys, identification of the genes that code for these transporters, and recognition of genetic syndromes related to these genes that alter BP regulation may result in the development of even better diuretics in the future.