The diuretics in our therapeutic armamentarium have predictable effects based on their nephron sites of action. All but spironolactone must reach the lumen or urinary side of the nephron to exert their effects. Thus, in settings of decreased renal function, doses must be increased to deliver more diuretic into the urine. In other edematous disorders, such as congestive heart failure (CHF) and cirrhosis, adequate amounts of diuretic reach the site of action if renal function is satisfactory. Diminished response in these conditions is caused by a decrease in the sensitivity of the nephron to the diuretic, the mechanism of which is unknown. Rather than using large single doses of diuretic in CHF and cirrhosis, multiple doses and/or combinations of diuretics should be used. Therefore, thiazide diuretics coupled with loop diuretics are most logical because they affect different nephron sites and the thiazide counteracts distal nephron hypertrophy that may occur with loop diuretics alone. Ample studies have shown that such combinations can result in a truly synergistic response. Using pharmacokinetics and pharmacodynamics of diuretics, we can design therapeutic regimens in which satisfactory control of fluid and electrolyte homeostasis can be achieved in the vast majority of patients.