A growing amount of evidence from animal and human studies supports a central role for the kidneys in the long-term control of blood pressure via the regulation of sodium excretion and body fluid volume. A pivotal part of the renal body fluid feedback control system for long-term volume and pressure regulation is the renal-pressure natriuresis mechanism. Renal-pressure natriuresis is abnormal (rightward shift) in all types of experimental and clinical hypertension. A shift of pressure natriuresis may occur as a result of intrarenal abnormalities such as enhanced formation of angiotensin II, reactive oxygen species, and endothelin (via ETA receptor activation) or decreased synthesis of nitric oxide or natriuretic prostanoids. In other instances, the altered kidney function is caused by extrarenal disturbances, such as increased renal sympathetic nervous activity or excessive formation of antinatriuretic hormones including aldosterone. Drugs used to treat hypertension reduce blood pressure by correcting and/or counteracting the intra- and/or extrarenal abnormalities that alter the pressure natriuresis relationship. Indeed, two new classes of glucose-lowering drugs, sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists, are thought to lower blood pressure through their renal actions.