The initial efficacy of long-acting nitrate preparations in the management of angina pectoris and congestive heart failure is well established. A high priority has been placed on determining whether tolerance to the early beneficial effects develops after long-term nitrate therapy. Experimentally, tolerance has been documented in in vitro studies and in intact animals, and the available evidence suggests that tolerance is a cellular phenomenon occurring in target tissue. From a critical review of the published literature and an analysis of our own clinical and experimental work, we conclude that partial tolerance to some of the hemodynamic effects of nitrates occurs after long-term administration. However, this class of drugs remains an important and effective therapeutic option in the treatment of patients with angina pectoris and congestive cardiac failure.