Vessel occlusion within a coronary artery is the precipitating event in unstable coronary syndromes and is primarily due to rupture of atheromatous plaque and subsequent thrombus formation. In the nondiseased vessel, the intact endothelium releases the vasodilator and antithrombotic agent nitric oxide (NO) preventing platelet adherence and activation. In the diseased vessel and during unstable coronary syndromes, release of both endothelial and platelet NO is impaired contributing to thrombus formation. Nitric oxide availability in the vascular system has been associated with various disease states, genetic variants, and medication use. Recently, through the development of new NO donors and by targeting specific signaling pathways, there has been an attempt to enhance the antithrombotic actions of NO as a means to manipulate arterial thrombosis.