Compared with substantial clinical research on the renin-angiotensin-aldosterone system (RAAS), much less is known about the importance of the sympathetic nervous system as a therapeutic target to slow the initiation and progression of human hypertension. Using microelectrode recordings of sympathetic activity and radiotracer measurements of regional norepinephrine spillover in hypertensive patients, recent research has advanced several provocative findings with novel—but still largely potential—therapeutic implications for clinical hypertension. These include a stronger scientific rationale for using 1) combined α/β-blockers in the early phases of primary hypertension and obesity-related hypertension; 2) RAAS blockers as central sympatholytics in hypertension associated with chronic kidney disease; and 3) a higher dialysis dose—either nocturnal or short daily hemodialysis—to reduce uremic stimulation of a blood pressure-raising reflex arising in the failing kidneys. New outcomes trials are needed if we are to translate this largely theoretical body of research into clinical practice.