Substantial evidence implicates impaired renal excretion of sodium as the major culprit in the pathogenesis of hypertension. The key question is: How does the impairment of Na+ excretion lead to increased peripheral vascular resistance and elevation of the blood pressure? Here we describe the evidence that elevated levels of a recently-discovered adrenal cortical hormone, endogenous ouabain, plays a central role in this process. This hormone inhibits the Na+ pump and raises intracellular Na+. Then, as a result of Na/Ca exchange, cytosolic Ca2+ and, more importantly, intracellular stores of Ca2+, are increased in vascular smooth muscle (VSM), vasomotor neurons, and endothelial cells, as well as in many other types of cells. Consequently, these cells become hyper-responsive because the cytosolic Ca2+ transients induced by cell activation are enhanced. The synergy of augmented sympathetic neuron transmitter release and augmented VSM cell responsiveness may account for the increased arterial tone and peripheral vascular resistance that is the hallmark of hypertension.