For many years the concept relating salt to blood pressure (BP) changes has been debated and the concept of natriuretic hormone eliminating excessive sodium by direct inhibition of Na/K-ATPase has raised controversy. However, a recently discovered Na/K-ATPase signaling function has been widely confirmed and provided a novel mechanism to explain the relationship between sodium and blood pressure. Recently, we have demonstrated that activation of this Na/KATPase signaling function regulates sodium reabsorption in renal proximal tubules (RPTs) to correct sodium retention related volume expansion and BP increase. This mechanism demonstrates that rather than contributing to development and maintenance of hypertension, a properly regulated RPT Na/K-ATPase signaling has a protective effect by stimulating renal sodium excretion. A clear understanding of molecular mechanisms whereby the Na/K-ATPase signaling axis counterbalance volume expansion would have major pathophysiological and therapeutic implications for volume expansion mediated hypertension. In this review, we will focus on the effect of the newly appreciated cardiotonic steroids (CTS)-Na/K-ATPase signaling on RPT-mediated sodium handling by coordinated regulation of the Na/K-ATPase and sodium/proton exchanger isoform 3 (NHE3).