Evidence for a 'third factor' in the regulation of urinary sodium excretion has directed a search for a natriuretic agent which functions by inhibition of Na,K-ATPase. Such an agent may also be involved in the genesis of hypertension and provide an important pathophysiological link between increased sodium intake, reduced renal sodium excretory capacity and hypertension. Numerous lines of evidence have been developed, all supporting the possibility that third factor sodium pump inhibition may take place through the cardiac glycoside-binding site of the sodium pump. Inhibition of the sodium pump may contribute to renal mechanisms of sodium balance. Generalization of this inhibition to vascular tissue and to the neural tissue regulating vascular contraction may elevate blood pressure (and increase natriuresis) by increasing contraction. In spite of 30 years of effort, no convincing substance has been successfully identified as both a cardiac glycoside-like inhibitor of the sodium pump and an endogenous substance. However, recent work has led to the emergence and investigation of a number of interesting candidates. This review will survey the historical background of endogenous sodium pump inhibitors, examine some of the problems and requirements which must be overcome in their identification, analyze evidence obtained recently concerning a number of candidate compounds and identify problems which remain to be addressed in this field.