It has been proposed that an unknown circulating factor inhibits the plasma membrane sodium-potassium pumps and thereby plays an important role as a natriuretic or vasoconstrictive agent in the regulation of volume and pathogenesis of low-renin hypertension. The sodium pumps have specific high-affinity receptors for the digitalis glyrosides. With the analogy of endogenous opioids and nitric oxide, this has fostered speculation that an endogenous ligand exists that is “digitalis-like.” Recently, an endogenous factor has been extracted from human plasma, has been purified, and has been structurally identified by mass spectroscopy. This factor binds with high affinity to the sodium pump receptor and is indistinguishable from the cardiotonic steroid ouabain. Considerable evidence suggests that ouabain is synthesized in the adrenal cortex. It has a basic steroid nucleus, it is detected in high concentration in adrenocortical tissue, a continuous venous-arterial gradient across the adrenal can be demonstrated in the dog, and after bilateral adrenalectomy, plasma ouabain levels fall significantly. Additionally, adrenocortical cells in culture synthesize ouabain de novo. A modest elevation in plasma ouabain has been demonstrated in various forms of hypertension in humans, and the chronic infusion of ouabain to raise the plasma level to a comparably modest degree produces reversible normal renin hypertension in the rat. Circulating ouabain may also prove to be important in heart failure and in the pathogenesis and evolution of primary aldosteronism. To date, the precise site in the adrenal cortex and pathways for the biosynthesis of ouabain have not been determined. This information and the clarification of the pressor mechanism and the significance of ouabain and other possible sodium transport inhibitors in disorders involving volume regulation are major areas for future research. Nevertheless, the presence of ouabain in the circulation and tissues suggests that it could prove to be of widespread biologic significance.