The circulating anion nitrite (NO(2)(-)), previously thought to be an inert product of nitric oxide (NO) oxidation, has now been identified as an important storage reservoir of bioavailable NO in the blood and tissues. Reduction of NO(2)(-) to NO over the physiologic pH and oxygen gradient by deoxyhemoglobin, myoglobin, xanthine oxidoreductase, and by nonenzymatic acidic disproportionation has been demonstrated to confer cytoprotection against ischemia-reperfusion injury in the heart, liver, brain, and kidney. Here, we review the mechanisms that have been established to regulate hypoxic NO(2)(-) reduction to NO, analyze the preclinical and clinical evidence supporting NO(2)(-)-mediated cytoprotection after ischemia-reperfusion injury, and examine the therapeutic potential of NO(2)(-) for cardiovascular disease. Evidence is accumulating that suggests NO(2)(-) has surmounted many of the direct challenges to reperfusion therapeutics summarized by the National Heart, Lung, and Blood Institute Working Group in "Myocardial protection at a crossroads: the need for translation into clinical therapy." In this context, we discuss important considerations in designing human clinical trials to test the efficacy of NO(2)(-) in the setting of ischemia-reperfusion injury, with particular attention to the study of ST-segment elevation myocardial infarction.