Essential hypertension is a very heterogeneous disease and different pressor mechanisms might interact to increase blood pressure. It is therefore not surprising that antihypertensive drugs given as monotherapies normalize blood pressure in only a proportion of hypertensive patients. This is, for instance, the case for diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor antagonists administered as single agents. The rationale for combining antihypertensive agents relates in part to the concept that the blood pressure-decreasing effect may be enhanced when two classes are coadministered. Also, combination treatment serves to counteract the counter-regulatory mechanisms that are triggered whenever pharmacologic intervention is initiated and act to limit the efficacy of the antihypertensive medication. For example, the compensatory increase in renin secretion induced by sodium depletion may become the predominant factor sustaining high blood pressure. Simultaneous blockade of the renin-angiotensin system, with either an ACE inhibitor or an AT1 receptor blocker, makes this compensatory hyper-reninaemia ineffective and allows maximum benefit from sodium depletion. The increased effectiveness obtained by combining a blocker of the renin-angiotensin system with a low dose of a diuretic is not obtained at the expense of reduced tolerability compared with the individual components administered alone. Fixed very-low-dose combinations containing an ACE inhibitor or an AT1 receptor blocker and a diuretic are therefore likely to become increasingly used, not only as second-line therapy, but also as first-line treatment. This is the case, for instance, for the fixed very-low-dose combination of the ACE inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), as this preparation is very effective in decreasing blood pressure while maintaining a tolerability that is similar to that of placebo.