Two thirds of patients with hypertension require more than one drug to achieve goal blood pressure. Rational antihypertensive drug combinations are based on their ability to produce additive blood pressure reduction and reduce the incidence of dose-dependent side effects. Some combinations exhibit side-effect neutralization in which side effects associated with one drug are neutralized by a second agent. Fixed-dose combinations improve adherence by reducing the number of pills and simplifying the treatment regimen. Because volume overload is common, low-dose diuretics are often included in drug combinations. Combinations of diuretics with potassium-sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and b-blockers are useful in treating large segments of the hypertensive population. Combinations of calcium channel blockers and angiotensin converting enzyme inhibitors are also effective and reduce the incidence of calcium blocker-related edema. Combinations of agents affecting the renin-angiotensin system by different mechanisms are currently the subject of active investigation.