Cardiovascular (CV) complications such as myocardial infarction, heart failure, stroke and renal failure are related to both the degree and the duration of blood pressure (BP) increase. Resistant hypertension (RH) is associated with a higher risk of CV complications and a higher prevalence of target organ damage (TOD). The relationship between CV disease and TOD can be bidirectional. Elevated BP in RH may cause CV structural and functional alterations, and the development or persistence of left ventricular hypertrophy, aortic stiffness, atherosclerotic plaques, microvascular disease and renal dysfunction, may render hypertension more difficult to control. Specifically, RH is related to several conditions, including obesity, sleep apnea, diabetes, metabolic syndrome and hyperaldosteronism, characterized by an overexpression of humoral and hormonal factors that are involved in the development and maintenance of TOD. Optimal therapeutic strategies, including pharmacological treatment and innovative invasive methodologies, have been shown to achieve adequate BP control and induce the regression of TOD, thereby potentially improving patient prognosis.