Summary: The question of whether or not the therapeutic efficacy of the nitrates is attenuated with chronic use has been studied mainly since the widespread use of controlled-release preparations for oral or transdermal administration, which lead to sustained high plasma nitrate concentrations. There are many possible reasons for the conflicting results published in regard to the clinical relevance of nitrate tolerance. Poor quality trials or inappropriate design should certainly be taken into account. Whether results obtained in laboratory circumstances, e.g., with maximal exercise testing in angina pectoris, are misleading with regard to the occurrence of attenuation in daily life circumstances is not likely but cannot be excluded. There is no evidence that attenuation is specific for one disease state or another, but interpatient differences in regard to the development of nitrate attenuation seem to exist. Nitrate tolerance is probably seen with all nitrate products. High and frequent dosing, but mainly use of controlled-release preparations for oral or transdermal administration, will favor the development of attenuation. In the many studies where nitrate-free periods are introduced, such regimens are found to be superior to regimens without a nitrate-free period. To obtain an antianginal effect during the nitrate-free period, and to avoid nitrate withdrawal phenomena, β-blockers or calcium antagonists should be used. Interest in using N-acetylcysteine to counteract nitrate tolerance is at this moment not proven.