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In 1984, the suspicion that pharmacological treatment may worsen the insulin resistance and associated metabolic abnormalities in lipid and carbohydrate metabolism and contribute to the relative failure of antihypertensive treatment to produce more than marginal reductions in cardiovascular morbidity and mortality led us to start a series of trials aimed at elucidating how antihypertensive drugs affect insulin sensitivity. These trials, which included assessment of insulin sensitivity by the euglycemic insulin clamp, showed that beta-adrenergic blockade and thiazide diuretic treatment (hydrochlorothiazide) increase insulin resistance and basal plasma insulin, whereas Ca(2+)-channel antagonists (verapamil and diltiazem), with the exception of the negative effect of nifedipine, are metabolically neutral. alpha-Adrenergic blockade with prazosin and angiotensin-converting enzyme (ACE) inhibition with captopril enhance insulin sensitivity. The mechanisms underlying the positive effects of ACE inhibition and beta-adrenergic blockade are largely unknown, but hemodynamic factors (vasodilation) may contribute by improving the access of glucose and insulin to skeletal muscle. The drugs, which were favorable or neutral with respect to insulin sensitivity, caused no changes in lipids or glucose homeostasis. In contrast, beta-blockers, except pindolol, had negative effects on triglycerides and high-density lipoprotein cholesterol, and thiazide diuretics caused adverse effects on total serum cholesterol, low-density lipoprotein cholesterol, and total and very-low-density lipoprotein triglyceride. The metabolic action of antihypertensive drugs is an important factor to consider in the choice of a proper treatment strategy in both diabetic and nondiabetic patients with hypertension.