Nitrates are used extensively for the treatment of angina pectoris. However, continuous therapy with either oral nitrates or nitroglycerin patches leads to rapid development of tolerance, with loss or diminution of antianginal and anti-ischemic effects. The only practical way to avoid the development of tolerance is to use intermittent daily therapy with nitrates. Nitroglycerin patches applied for 10-12 hours during the day increase exercise duration for 8-12 hours, but a rebound increase in anginal attacks during the nitrate-free interval may occur. Oral isosorbide-5-mononitrate, 20 mg twice a day, with the first dose administered in the morning and the second dose 7 hours later, increases exercise duration for at least 12 hours without the development of tolerance to either the morning or afternoon dose. This dosing regimen has been shown not to produce a rebound phenomenon during the periods of low nitrate levels at night and early hours of the morning. Isosorbide dinitrate (30 mg) prescribed at 7 AM and 1 PM does not produce tolerance to the 7 AM dose, but effects of the afternoon dose have not been evaluated. Recent data suggest that isosorbide dinitrate given 3 or 4 times daily produces tolerance and this dosing schedule is inadequate for antianginal prophylaxis. It should be recognized that intermittent oral or patch therapy with nitrates during the day leaves the patient unprotected at night and early hours of the morning. If this is of concern, additional therapy with another class of antianginal agent, preferably a long-acting beta blocker or a long-acting calcium antagonist should be instituted.