Na+,K+-ATPase distributes ions between the intracellular and extracellular space and is responsible for total-body sodium homeostasis. The activity of this ion pump is regulated by catecholamines and peptide hormones; by the ligand of Na+,K+-ATPase, ouabain; and by direct interaction with cytoskeleton proteins. This review summarizes recent advances in the field of short-term regulation of Na+,K+-ATPase and the implications of these advances for the regulation of blood pressure. Renal Na+,K+-ATPase activity is bidirectionally regulated by natriuretic and antinatriuretic hormones, and a shift in the balance between these forces may lead to salt retention and hypertension. Dopamine plays a key role in this interactive regulation. By inhibiting vascular Na+,K+-ATPase activity, an excess of circulating ouabain may increase calcium concentration in vascular cells and lead to increased vascular contractility. Finally, mutations in cytoskeleton proteins may stimulate renal Na+,K+-ATPase activity by way of protein/protein interaction and lead to salt retention and hypertension. Abnormalities in the systems regulating Na+,K+-ATPase should be explored further in the search for the multiple causes of essential hypertension.