Recent guidelines are consistent in acknowledging that most hypertensive patients need at least two drugs for optimal blood pressure (BP) control. Trial data are available to support the use of a renin-angiotensin system (RAS) blocker (ie, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker), plus a diuretic, a RAS blocker plus a calcium channel blocker (CCB), and a CCB plus a diuretic. The ACCOMPLISH trial demonstrated somewhat convincingly that an ACE inhibitor/CCB is superior to the same ACE inhibitor plus a thiazide. In the ASCOT trial, amlodipine/perindopril was superior to beta-blocker/thiazide in its effects on all major cardiovascular outcomes and new-onset diabetes. Further substudies of ASCOT provided plausible explanations for the benefits of amlodipine/perindopril strategy. In the CAFE substudy, amlodipine/perindopril was significantly more effective in the reduction of central BP as compared to atenolol/bendroflumethiazide, despite similar brachial BP reduction. More recently, analysis of long-term BP variability provided a further explanation for the reduction of cardiovascular events with amlodipine/perindopril in ASCOT. Thus, the combination of perindopril and amlodipine seems an ideal logical evidence-based pair of antihypertensive agents to select.