Atrial natriuretic factor (ANF) is a hormone with the physiological characteristics of a regulator of body fluid volume. It is potent, has a short duration of action, and responds to a physiologically relevant stimulus in a negative feedback-controlled system. It can act directly or indirectly (via inhibition of aldosterone biosynthesis) on the kidney to alter sodium transport and may regulate fluid distribution within the extracellular space. The peptide circulates at low (nanomolar) levels, and recent studies with renal inner medullary cells document relevant receptor binding and second messenger activation in this concentration range. In vivo data support a direct action on the kidney to enhance natriuresis, and blockade of a primary catabolic pathway for ANF within the kidney results in augmented natriuresis at concurrent endogenous peptide concentrations. Long-term, low dose infusion directly into the renal artery of conscious dogs supports a physiological action of ANF to promote urinary sodium excretion. Nevertheless, under certain circumstances, natriuresis does not occur even at high circulating levels of ANF. Apparently other factors such as renal perfusion pressure, volume status, and renal nerve activity are important in determining the natriuretic response to a given level of peptide. We hypothesize that the role played by ANF in volume regulation is highly complex, and the kidney responds with increased sodium excretion only when a constellation of variables is appropriately arrayed. That is, ANF is a necessary, but not sufficient, condition to induce natriuresis. {Hypertension 1990;15:2-8) W hen the first cell wrapped itself in a membrane, volume regulation became a key to survival. The factors controlling body fluid volume (e.g., the balance between intake and output of salt and water) are many and complex. Intake is mediated through thirst and salt appetite, whereas output is a complex interplay of variables that primarily affect renal function. Historically, the factors considered important for regulation of the renal output of salt and water are glomerular filtration and the facilitated reabsorption of sodium by aldosterone.The actions of aldosterone in regulating sodium reabsorption from the nephron and changes in glomerular filtration have not proven adequate to explain all of the experimental findings related to extracellular volume control. Based on the compelling experiments of DeWardener et al, 1 in which it was shown that the natriuresis associated with saline volume expansion was not prevented by controlling filtration and aldosterone levels, the concept of a salt-excreting reflex pathway was established. Presumably, there