Organic nitrates have been used for the treatment of ischemic heart diseases for more than 100 years and these drugs are still amongst the most frequently prescribed and applied drugs worldwide. Development of tolerance against the hemodynamic effects of nitrates during sustained therapy, however, limits their clinical application. Moreover, recent clinical studies have suggested that long-term nitrate treatment does not improve or may even worsen cardiovascular mortality, possibly due to the development of vascular nitrate tolerance. In agreement with these clinical findings, nitrate tolerance has been shown to increase superoxide and peroxynitrite production leading to vascular dysfunction. Nevertheless, nitrates exert a direct myocardial anti-ischemic effect that is independent from their vascular actions. The direct myocardial effect of glyceryl trinitrate (GTN) has been shown to be preserved even in the state of vascular nitrate tolerance. Moreover, no oxidative stress was observed in hearts isolated from rats with vascular nitrate tolerance, while increased systemic peroxynitrite formation was detected in the plasma in the same animals. The different effects of nitrates on the heart and vasculature are not well characterized; however, tissue specific differences in the metabolism and cellular signaling of nitrates might be a plausible explanation. These data suggest that sustained nitrate treatment increases oxidative stress in the extracardiac vasculature, thereby promoting the development of vascular nitrate tolerance. However, the direct myocardial anti-ischemic effect of nitrates seems to be preserved beyond the development of vascular nitrate tolerance. These new findings may open new perspectives in the clinical use of organic nitrates and suggest that the development of either cardioselective nitrates or nitrate-antioxidant hybrid drugs may replace classical nitrates in the therapy of ischemic heart disease.