Background: Resistant hypertension is defined when the blood pressure remains elevated above the therapeutic target levels despite the use of three antihypertensive agents including calcium channel blocker (CCB), renin-angiotensin system (RAS) blocker and a diuretic. These drugs should be used at maximally tolerated doses and white coat effect and non-adherence should also be excluded. In this article, by describing a case of resistant hypertension, we discuss a diagnostic and therapeutic approach to resistant hypertension. Case Presentation: A 59 years old man, known case of diabetic nephropathy with a serum creatinine level of 1.2 mg/dL and proteinuria of about 3300 mg in 24 hours referred to Hypertension Clinic of Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, for evaluation of resistant hypertension. The patient was under treatment by losar-H, diltiazem, and furosemide, which are not appropriate combinations of antihypertensive agents. The ambulatory blood pressure monitoring (ABPM) of the patient revealed daytime and nighttime hypertension and also the non-dipping status of blood pressure. Dihydropyridine CCB was prescribed in combination with RAS blocker (Exforge 50 mg/ 160 mg) and the diuretic was changed to thiazide-like agents. In the next step, spironolactone and carvedilol were added for better control of blood pressure. The patient referred to the sleep clinic for polysomnography and evaluation of obstructive sleep apnea. Following three months prescription of these medications, ABPM revealed relatively appropriate control of blood pressure, so the average 24-hour blood pressure decreased from 157/91 mm Hg to 136/83 mm Hg. Conclusion: The complications and mortality of hypertension would be increased dramatically in patients with resistant hypertension. So, an appropriate diagnostic and therapeutic approaches should be considered for these patients. Choosing appropriate diuretic agents would be important in the management of resistant hypertension.