The period from 1951 to 1957 saw a unifying shift toward hormonal control of renal sodium handling as the central determinant of diuretic response and resistance. Aldosterone emerged as the principal regulator of distal nephron sodium reabsorption, linking mineralocorticoids to edema and volume retention and reframing diuretic resistance as a hormonally mediated process. The identification of primary aldosteronism revealed a distinct syndrome of mineralocorticoid excess causing hypertension, guiding diagnostic workups and influencing therapeutic approaches to diuretic management. The development of benzothiadiazine dioxides as a new diuretic class targeted distal tubule sodium reabsorption, countering aldosterone-driven retention and transforming treatment of edema and diuretic resistance. Observations of an antidiuretic hormone–related hyponatremia syndrome further highlighted hormonal control beyond aldosterone as a factor in diuretic response, signaling the need for integrated, hormone-informed strategies in resistant hyponatremia. Collectively, these themes illustrate a research consolidation around endocrine regulation of fluid balance and its implications for therapy.