The phenomenon of nitrate tolerance has now been appreciated for almost a century, and our understanding of this process has greatly improved during the past 20 years. Therapeutic nitrates are now recognized as exogenous sources of nitric oxide (or nitrosothiols), which appears to be a primary mediator of natural vasodilatation. Nitrates have been clearly shown to have vasodilatory and antiplatelet effects, both of which diminish during continuous exposure. Nitrate tolerance has been documented with most nitrate preparations when the patient is given continuous nitrate therapy. Tolerance to nitrates may occur in any patient, regardless of underlying illness, medication dose, or serum concentration of NTG. The cause of this phenomenon is multifactorial; there appear to be both cellular and systemic processes involved. To date, no adjuvant pharmacologic intervention has conclusively demonstrated benefit in preventing, abating, or reversing nitrate tolerance. Interruption of nitrate exposure for as little as 8 to 12 hours does appear to be the best means of preventing or reversing tolerance. Nevertheless, some patients with objective tolerance continue to experience relief of symptoms. In addition, despite laboratory-documented cross-tolerance, patients receiving continuous nitrate therapy at usual clinical doses may continue to benefit from the hemodynamic and antianginal effects of SL NTG. Hence, nitrate tolerance is a real entity, but the clinical importance of this phenomenon remains controversial. Finally, further investigation will need to address quality-of-life issues and perhaps assess relief of ischemia by other means. © 1994.