Hypertension remains an important problem that increases the risk of cardiovascular disease and is a leading cause of mortality worldwide. Achieving long-term control of arterial hypertension, which has an estimated prevalence of 28% in the US adult population, would translate into a significant reduction in cardiovascular events. Specific causes can be identified and treated for certain forms of secondary hypertension, but often it is multifactorial. Therefore, it makes sense to attain blood pressure control by addressing more than one pressor mechanism. Several clinical studies have demonstrated that combination antihypertensive therapy is more effective than monotherapy, and a review of currently published data suggests that approximately 75% of hypertensive individuals will require some form of combination therapy to achieve target blood pressure (BP) goals. To this end, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of Blood Pressure (JNC 7) has recommended that antihypertensive therapy should start with two drugs when a patient presents with systolic blood pressure (SBP) more than 20 mm Hg above target levels, diastolic blood pressure (DBP) more than 10 mm Hg above target levels, or both. This review attempts to analyze the current evidence in published medical literature to answer the question of whether hydrochlorothiazide or a calcium channel blocker is a better add-on to a renin-angiotensin system blocker for treating hypertension in patients with renal disease.