Nitric oxide (NO) is a potent biological mediator possessing a variety of properties relevant for cardiovascular protection, such as vasodilation, inhibition of platelet adhesion and aggregation, and prevention of smooth muscle cell proliferation. Numerous cells in the bloodstream, including red blood cells, platelets, and white blood cells, as well as endothelial cells (the largest source) release NO. Conditions that impair the production or bioavailability of NO can increase the risk of arterial and venous thrombosis. Therefore, using NO as an antithrombotic agent seems logical. However, due to its very short half-life, limited solubility in water, and radical nature, it cannot be used as such and thus several chemical strategies have been developed to create drugs that release NO or enhance its endogenous production/bioavailability. In this chapter, we review the pharmacological strategies aimed at increasing endogenous NO or inducing NO release developed over the past decades, and the effects of these drugs on platelet activation in vitro, and in vivo in animal thrombosis models and in humans. A key challenge in developing NO-releasing agents as antithrombotic drugs is their associated vasodilatory effect, which can induce hypotension and thus limit their use. Continued pharmacological and clinical research into novel NO-enhancing and/or releasing compounds is essential to fully exploit therapeutically the great antithrombotic potential of NO.