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 monotherapy, normalize blood pressure in only a fraction of hypertensive patients. This is, for instance, the case for diuretics, angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AT1) receptor antagonists administered as single agents. The rationale for combining antihypertensive agents relates in part to the concept that the blood pressure-lowering effect may be enhanced when two classes are coadministered. Also, combination therapy serves to counteract counter-regulatory mechanisms that are triggered whenever pharmacologic intervention is initiated and that act to limit the efficacy of the antihypertensive medication. For example, the compensatory rise 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-reninemia ineffective and allows maximum benefit from sodium depletion. The combination of a blocker of the renin-angiotensin system and a low dose of a diuretic increases the effectiveness, but not at the expense of tolerability compared with the individual components administered alone. Fixed-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.