Despite the availability of many effective antihypertensive drugs, the drug therapy for resistant hypertension remains a prominent problem. Reviews offer only the general recommendations of increasing dosage and adding drugs, offering clinicians little guidance with respect to the specifics of selecting medications and dosages. A simplified decision tree for drug selection that would be effective in most cases is needed. This review proposes such an approach. The approach is mechanism-based, targeting treatment at three hypertensive mechanisms: (1) sodium/volume, (2) the renin-angiotensin system (RAS), and (3) the sympathetic nervous system (SNS). It assumes baseline treatment with a 2-drug combination directed at sodium/volume and the RAS and recommends proceeding with one or both of just two treatment options: (1) strengthening the diuretic regimen, possibly with the addition of spironolactone, and/or (2) adding agents directed at the SNS, usually a β-blocker or combination of an α- and a β-blocker. The review calls for greater research and clinical attention directed to: (1) assessment of clinical clues that can help direct treatment toward either sodium/volume or the SNS, (2) increased recognition of the role of neurogenic (SNS-mediated) hypertension in resistant hypertension, (3) increased recognition of the effective but underutilized combination of α- + β-blockade, and (4) drug pharmacokinetics and dosing. J Clin Hypertens (Greenwich). 2011;13:120–130. © 2010 Wiley Periodicals, Inc.