The pathophysiology of sodium and water retention in heart failure is characterized by a complex interplay of hemodynamic and neurohumoral factors. Relative arterial underfilling is an important signal that triggers heart failure-related sodium and water retention. The response to perceived arterial underfilling is modulated by the level of neurohormonal activation, the degree of renal vasoconstriction, and the extent to which renal perfusion pressure is reduced. Sodium retention can also be exceeded by water retention, with the result being dilutional hyponatremia. Sodium and water retention in heart failure also function to dampen the natriuretic response to diuretic therapy. The attenuated response to diuretics in heart failure is both disease-specific and separately influenced by the rate and extent of diuretic absorption, the rapidity of diuretic tubular delivery, and diuretic-related hypertrophic structural changes that surface in the distal tubule.