Plasma renin activity (PRA)-guided therapy has been proposed as a strategy for selecting antihypertensive medications matched to the patient's underlying pathophysiology. To date, there are only a few studies that have sought to compare a PRA-guided strategy to usual care. In one trial of 363 untreated patients, based on home blood pressure (BP) averages, PRA was predictive of responses to beta-blocker and thiazide diuretic as monotherapy and add-on therapy. In another trial of 77 treated but uncontrolled patients, a PRA-guided strategy was superior to clinical hypertension specialist care for guiding add-on or subtraction (stopping an agent that might cause a paradoxical pressor response) therapy. In the ValVET study, PRA-guided therapy was not superior to fixed-dose therapy consisting of an angiotensin receptor blocker and hydrochlorothiazide. One modeling study found a PRA-guided strategy may be cost-effective compared to standard care for younger patients and those with a greater number of cardiovascular risk factors. We conclude that additional, well-designed randomized trials with sufficient sample sizes comparing PRA-guided management to usual care are needed to clarify whether this strategy should be adopted broadly.