Resistant hypertension (RH) is frequently encountered in primary care practice and often presents a significant clinical challenge because limited evidence-based guidance exists. RH is a major cause of cardiovascular disease and death, and has been associated with a 50% increased risk of myocardial infarction, stroke, congestive heart failure, and chronic kidney disease when compared to patients without RH. The American Heart Association defines RH as uncontrolled BP despite maximal treatment with a three-drug regimen, ideally including a diuretic. The exact prevalence of RH is unknown, but large randomized controlled trials suggest it affects one in five patients with elevated BP. Previous research findings suggest chlorthalidone, spironolactone, and eplerenone are all effective add-on therapies when BP remains uncontrolled with typical first line agents. The Pathway-2 study provides the first direct comparative evaluation of three different four-drug antihypertensive regimens.