The publication of the results of the Swedish Trial in Old Patients with Hypertension-2 (STOP-2) and the termination of the doxazocin arm of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) study again raise the question of whether all antihypertensives deliver equal cardiovascular outcome benefits. Data from research on congestive heart failure and from the Heart Outcomes Prevention Evaluation (HOPE) trial illuminate the roles and possible mechanisms of humoral mediators of vascular damage, suggesting, first, that some antihypertensives (thiazides, beta-blockers, and angiotensin-converting enzyme inhibitors) can deliver more improvement in outcomes than other agents and, second, that decisions on whom to treat are best made based on risk appraisal, not merely pressures.