The pathogenesis of renal sodium and water retention in cardiac failure, cirrhosis, and the nephrotic syndrome may be explained by the unifying hypothesis of body fluid volume regulation. According to this hypothesis, underfilling of the arterial vascular compartment initiates a sequence of events, including activation of various neurohormonal vasoconstrictor systems, which results in enhanced renal sodium and water reabsorption, the failure to escape from the sodium-retaining effect of aldosterone, and renal resistance to atrial natriuretic peptide. In patients with low-output cardiac failure, a decrease in cardiac output results in arterial underfilling. Peripheral arterial vasodilation diminishes the fullness of the arterial vascular compartment in patients with high-output cardiac failure and cirrhosis. In the nephrotic syndrome, the decrease in plasma oncotic pressure due to hypoalbuminemia initiates arterial underfilling. The factors that are responsible for the peripheral arterial vasodilation in patients with cirrhosis remain obscure. Diuretics are initially effective in reducing the excess of total-body sodium and water in edematous patients. Loop diuretics, with or without metolazone or a thiazide diuretic, are quite useful in patients with heart failure. In cirrhosis and the nephrotic syndrome, the specific aldosterone antagonist spironolactone, alone or in combination with other diuretics, has proven to be highly efficacious. However, in all instances, the emergence of diuretic resistance represents a major limitation of diuretic therapy for the edematous patient. This diuretic resistance may be mediated by further activation of vasoconstrictor, antinatriuretic neurohormones.