Nitrates have been used in clinical cardiovascular medicine for >100 years. The phenomenon of nitrate tolerance has been known for almost as long, but it has only become important relatively recently, with the increasing use of nitrates in angina pectoris, myocardial infarction, and heart failure. This article examines the differing effects of nitrates, ranging from cellular effects, through coronary and vascular effects, to the recently confirmed antiplatelet actions. The theories put forward to explain nitrate tolerance are examined, including recent work on vascular superoxide and endothelin-1 regulation. Information on tolerance obtained from in vitro or in vivo animal experiments must, however, be interpreted with caution. Clinically, tolerance can be prevented by intermittent dosing of nitrates. This topic, and the results of work using other pharmacologic interventions in a clinical setting are discussed in the final section of this paper.