Refractory or resistant hypertension is conventionally defined as systolic or diastolic blood pressure that remains uncontrolled despite sustained therapy with at least three different classes of antihypertensive agents. Refractory hypertension is estimated to affect less than 5% of the general population with hypertension; however, its prevalence increases with increasing severity of blood pressure. Patients presenting with refractory hypertension usually have progressed from mild, to moderate, to severe hypertension because of lack of or inadequate treatment. Other common contributing factors include obesity, medical nonadherence, suboptimal medical regimens, excessive dietary salt ingestion, secondary forms of hypertension, sleep apnea, and ingestion of substances that interfere with treatment. Combination therapy that includes appropriate doses of a diuretic is recommended for treatment of refractory hypertension. Use of fixed-dose combinations enhances compliance through cost savings, more convenient dosing, and reduced pill burdens.