In this article, we emphasize our studies on animals and humans and those in the literature on humans that bear on the possible role of a circulating Na+-K+ pump inhibitor in the mechanism of hypertension. An effort is made to determine the features most likely to be associated with evidence for elevated levels of this inhibitor. The data from animals indicate that these features are reduced capacity to excrete salt (functional or organic), increased salt intake, increased extracellular fluid volume, and low plasma renin activity. The data from humans suggest but do not prove that the inhibitor is most likely to be found in males with increased sodium intake, decreased renal function, and decreased plasma renin activity. In future studies on hypertensive humans we should pay more attention to the characteristics of the patients (sex, race, age, drug therapy, stage of hypertension, sodium intake, renal function, and renin status) and make a more vigorous effort to match these patients properly with normotensive control subjects.