International Journal of Hypertension (iv) Evaluation for Secondary Causes of Hypertension. As previously discussed, obstructive sleep apnea, primary aldos- teronism, and chronic kidney disease represent the most common secondary causes of resistant hypertension whereas several other conditions may be responsible for treatment resistance as well. The diagnostic workup for secondary hypertension is demanding, requires special knowledge and technology, and should be performed in specialized referral centers, which are familiar with secondary hypertension. Although a detailed description of the diagnostic workup is beyond the scope of this paper, some signs and/or ﬁndings raising the suspicion of secondary hypertension need to be mentioned. In particular: obesity, snoring, daytime sleepiness, and increased neck diameter raise the suspicion of obstructive sleep apnea; hypokalemia (either spontaneous or diuretic induced) is present in about half of cases with primary aldosteronism; active urine sediment, small kidneys, and impaired renal function point towards chronic kidney disease; abdominal bruit, diﬀerence in renal size raise the suspicion of renal artery stenosis.. (v) Pharmacologic Management of Resistant Hypertension. The pathophysiology of resistant hypertension provides the rational for the eﬀective management of this clinical entity. The combination of increased systemic vascular resistance with marked volume expansion in many cases, renders the triple combination of a drug inhibiting the renin- angiotensin axis (ACE-inhibitors or angiotensin receptor blockers) with a calcium antagonist and a diuretic a very attractive combination for the majority of patients (unless these drugs are contraindicated or not tolerated, or other drugs are indicated due to comorbidities). However, reliable data verifying the superiority of this combination over other combinations is not available. Special attention has to be drawn in maximizing the dose of diuretics or switching to loop diuretics in patients with low GFR. The overactivation of the sympathetic nervous system renders beta blockers, alpha blockers, and centrally acting antihypertensive drugs (clonidine, alpha methyldopa) of potential beneﬁt in many patients when added in previous therapy. Direct vasodilators, such as hydralazine and minoxidil, can be very eﬀective for blood pressure management, especially in African Americans and patients with chronic kidney disease. A vast amount of evidence indicates that spironolactone is a drug of choice in the treatment of resistant hypertension. Several studies revealed impressive blood pressure reductions in patients with resistant hypertension when spironolactone was added in the therapeutic regime [195–205]. Chronotherapy rep- resents an important approach for the management of resistant hypertension. Administration of one antihyperten- sive drug at bedtime has been shown to improve blood pressure control in patients with resistant hypertension [206–208]. (vi) Newer Drugs for the Management of Resistant Hyperten- sion . Endothelin antagonists exhibited promising results in preliminary studies [209]. The future of darusentan remains unclear, however, since in another study in patients with 9 resistant hypertension, darusentan failed to be more eﬀective than placebo regarding oﬃce blood pressure reductions. It has to be mentioned, however, that in the latter study, signiﬁcant diﬀerences were detected in ambulatory blood pressure between darusentan and placebo [210], indicating that further studies are needed with this drug category. Another interesting approach for the management of resis- tant hypertension is the administration of nitric oxide donors. In a recent small clinical study of six patients with resistant hypertension, the combination of nitrates with phosphodiesterase-5 inhibitors resulted in signiﬁcant blood pressure reduction [211]. However, this ﬁnding has to be interpreted with caution, since the concomitant use of these medications is contraindicated due to the possibility of severe hypotension. (vii) Interventional Management of Resistant Hypertension. Despite the wide application of antihypertensive therapy, a substantial portion of the hypertensive population remains uncontrolled although taking more than three drugs. This situation calls for testing alternative approaches in patients with resistant hypertension. Carotid baroreceptors and renal sympathetic overdrive play a signiﬁcant role in blood pres- sure regulation [212, 213]. During the last decade, two new approaches have revived the use of interventional techniques for the management of resistant hypertension. Carotid baroreceptor stimulation and renal sympathetic denervation have shown promising preliminary results in patients with resistant hypertension [214, 215]. However, further studies are needed to establish their role in the management of resistant hypertension. References [1] P. M. Kearney, M. Whelton, K. Reynolds, P. Muntner, P. K. Whelton, and J. He, “Global burden of hypertension: analysis of worldwide data,” Lancet, vol. 365, no. 9455, pp. 217–223, 2005. [2] D. 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