Resistant hypertension (RH) is defined as an uncontrolled office blood pressure (BP) despite the use of at least three antihypertensive drugs. With an increasing prevalence, RH implies in a very high cardiovascular risk and needs a careful clinical approach, aiming to control BP and to reduce its morbidity and mortality. The initial diagnostic approach involves drug adherence checking and the evaluation of antihypertensive scheme, emphasizing the use of diuretics and adequate combination and dosages of the two other drugs, which preferentially reduces cardiovascular risk and promotes prevention/regression of target organ damages. Because of an exaggerated white-coat effect, ambulatory BP monitoring (ABPM) at baseline is mandatory to classify patients into true RH (uncontrolled ambulatory BPs) and white-coat RH (controlled ambulatory BPs), and define initial therapeutic approach. Ideally, the objective is ambulatory BP control, so the treatment follow-up shall be based on ABPM measurements. The treatment involves lifestyle changes and use of adequate combinations of antihypertensive agents from different classes. In this way, patients with true RH need to intensify antihypertensive treatment by adding aldosterone antagonists as the fourth drug and also changing antihypertensive treatment to bedtime. Otherwise, in patients with controlled ambulatory BP, the therapeutic scheme should be maintained and ABPM or home BP monitoring repeated serially. Despite pharmacological interventions, ambulatory BP control in RH patients remains challenging and new interventional procedures have been recently proposed, as renal denervation and baroreflex activation therapy. Currently, these procedures shall be reserved to true RH patients in whom other alternatives have failed.