The incidence of resistant hypertension, the failure to reduce blood pressure below 140/90 mm Hg, despite the use of 3 antihypertensive medications at optimal doses including a diuretic, is estimated to be less than 5% of the hypertensive population. Resistant hypertension increases the risk of stroke, myocardial infarction, congestive heart failure, and renal failure. Evaluation of the patient with resistant hypertension should include 24-hour ambulatory blood pressure monitoring or home measurements and a limited search for secondary causes. Treatment should focus on optimizing the drug regimen in a logical way, based on the patient's comorbidities and tolerability. Long-acting, well-tolerated once-daily medications are preferred, and the regimen should include in sequence a diuretic, beta-blocker, angiotensin-converting enzyme/angiotensin receptor-blocker inhibitors, and a calcium-channel blocker. This article reviews the definitions and causes and provides specific recommendations for the evaluation and management of patients with this life-threatening condition.