Cigarette smoking increases heart rate, arterial blood pressure, and plasma catecholamine levels. In healthy subjects the increase in heart rate occurs in the absence of peripheral vasoconstriction. In the studies reported here, short-term beta-blockade increased peripheral vascular resistance during smoking, more so for the nonselective beta-blocker propranolol than for the beta 1-selective blocker atenolol. However, after 3 months of continuous treatment of hypertensive patients with beta-blockers, smoking produced similar increases in blood pressure for atenolol and propranolol. Smoking attenuated the beneficial blood pressure-lowering effect of beta-blockers. Short-term clinical studies with the nonselective alpha-inhibitor phentolamine have suggested that blockade of arteriolar alpha-receptors may eliminate the increase in blood pressure response to smoking. Treatment with alpha-inhibitors also increased coronary sinus blood flow in patients with atherosclerotic artery disease. For patients who smoke, alpha-inhibiting drugs may provide beneficial therapy for hypertension and other cardiovascular disorders.