Two prescient 1953 publications set the stage for elucidating a novel endocrine system: Schatzmann's report that cardiotonic steroids (CTSs) are all Na⁺ pump inhibitors, and Szent-Gyorgi's suggestion that there is an endogenous "missing screw" in heart failure that CTSs like digoxin may replace. In 1977 I postulated that an endogenous Na⁺ pump inhibitor acts as a natriuretic hormone and simultaneously elevates blood pressure (BP) in salt-dependent hypertension. This hypothesis was based on the idea that excess renal salt retention promoted the secretion of a CTS-like hormone that inhibits renal Na⁺ pumps and salt reabsorption. The hormone also inhibits arterial Na⁺ pumps, elevates myocyte Na⁺ and promotes Na/Ca exchanger-mediated Ca²⁺ gain. This enhances vasoconstriction and arterial tone - the hallmark of hypertension. Here I describe how those ideas led to the discovery that the CTS-like hormone is endogenous ouabain (EO), a key factor in the pathogenesis of hypertension and heart failure. Seminal observations that underlie the still-emerging picture of the EO-Na⁺ pump endocrine system in the physiology and pathophysiology of multiple organ systems are summarized. Milestones include: 1. Cloning the Na⁺ pump isoforms and physiological studies of mutated pumps in mice; 2. Discovery that Na⁺ pumps are also EO-triggered signaling molecules; 3. Demonstration that ouabain, but not digoxin, is hypertensinogenic; 4. Elucidation of EO's roles in kidney development and cardiovascular and renal physiology and pathophysiology; 4. Discovery of 'brain ouabain', a component of a novel hypothalamic neuromodulatory pathway; 5. Finding that EO and its brain receptors modulate behavior and learning.