Thiazides and compounds with similar models of action exert their most important renal effects on the cortical-diluting segment of the nephron, most likely from the peritubular side. In contrast, the most important site of action of loop-diuretics is the luminal side of the ascending part of the diluting segment. The different sites of action explain the clinically proven efficacious combination of thiazides and loop-diuretics in severe cardiac failure. Most thiazides and loop-diuretics are eliminated via renal tubular secretion, which leads to decreased renal clearance in patients with chronic heart failure (CHF) as their renal blood flow is decreased even if glomerular filtration rate (GFR) is maintained. A rational approach to enhance the effects of loop-diuretics is to combine them with drugs that increase renal blood flow, thereby increasing the rate of delivery of the drug to its site of action. Dilutional hyponatremia is an important complication of treatment with diuretics. An efficacious treatment of that condition seems to be a combination of loop-diuretics and ACE-inhibitors. Thiazides decrease the urinary excretion of calcium, while loop-diuretics have the opposite effect. The possibility of loop-diuretic induced osteopenia cannot be ruled out, which should be considered when choosing between thiazides and loop-diuretics for the treatment of mild to moderate CHF.