The sodium pump is a ubiquitous cell surface enzyme, a Na/K-ATPase, that maintains ion gradients between cells and the extracellular fluid. The extracellular domain of this enzyme contains a highly conserved receptor for a plant-derived family of compounds, the digitalis glycosides, used in the treatment of congestive heart failure, and certain cardiac arrhythmias. The concept that an endogenous modulator of this enzyme, analogous to the cardiac glycosides, emerged from work on two separate areas: the regulation of extracellular fluid (ECF) volume by a natriuretic hormone (NH), and the regulation of peripheral vascular resistance by a circulating inhibitor of vascular Na/K-ATPase. These two areas merged with the hypothesis that natriuretic hormone and the vascular Na/K-ATPase inhibitor were the same factor, and furthermore, that this factor played a causative role in the pathophysiology of certain types of hypertension. In this communication, the development of this field from its beginnings is traced; evidence for the existence of and efforts to identify the structure of this factor are briefly reviewed, and suggestions for future development of the field are put forward.