One of the current recommendations for the treatment of hypertension is a stepped-care approach in which a second drug is added to a first-line agent when adequate blood pressure control has not been achieved. It has been well demonstrated in multiple studies that the response rate to any single class of antihypertensive agent, given as monotherapy, is approximately 45–55%. Thus, in approximately half of the hypertensive population, a second drug will be required. This is not surprising, since it is now well recognized that hypertension is a multifaceted disease process. The use of combination therapy with low-dose diuretics ( 25mg hydrochlorothiazide [HCTZ]or its equivalent) has become a very attractive alternative choice to first-line therapy. The data from clinical trials clearly demonstrate that 6.25 mg or 12.5 mg HCTZ has an additive or synergistic effect on blood-pressure reduction when used in combination with most drugs. At low doses, the side-effect profile with diuretics is similar to placebo. Furthermore, metabolic side effects are significantly reduced when diuretics are used in low doses. The use of low-dose diuretics in combination with other first-line agents significantly enhances blood-pressure control and reduces the likelihood of adverse events and alteration in carbohydrate, lipid, and electrolyte metabolism. Thus, combination therapy with low-dose diuretics provides an attractive alternative approach to first-line treatment of essential hypertension.