Many of the estimated 50 million Americans with high blood pressure receive medications for hypertension and for other conditions, placing them at risk for adverse drug interactions. The risk for hypertension and for adverse drug reactions is highest in the elderly, who have the greatest need for pharmacologic therapy. The most important class of drug interactions involves the cytochrome P450 microsomal enzyme system, which handles a variety of xenobiotic substances. A potential for interactions with these enzymes exists with calcium channel blockers, beta-adrenergic blocking agents, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers but not with diuretic antihypertensives, which are renally eliminated and more vulnerable to drug interactions that occur in the kidney. This article reviews the cytochrome P450 enzyme system, identifies drugs and foods that have been implicated in metabolic interactions with antihypertensive agents, and suggests measures for reducing the risk of adverse events when drugs are coadministered.