The antithrombotic activity of dipyridamole was initially discovered in an in vivo experiment about half a century ago. At that time science had not appreciated the complexity of the regulation of local thrombus formation. Inhibition of platelets has been the main focus for the prevention of arterial thrombus formation. Unfortunately, established in vitro test systems have to take away several important components of the hemostatic system. Rather than directly inhibiting platelet aggregation, dipyridamole amplifies endogenous antithrombotic systems and modulates or downregulates prothrombotic processes. While for many years the main focus had been on preventing acute thrombus formation in the case of a rupture of an atherosclerotic plaque in large coronary arteries, it now has been appreciated that perfusion of tissue and patency of small vessels and capillaries is equally important for preventing further damage to the tissue. Here dipyridamole was experimentally shown to improve perfusion and function in chronic hypoperfused tissue unrelated to its vasodilatory properties. Recently, several clinical trials have shown the benefit of dipyridamole when given in a formulation that assures a sufficient plasma concentration. Its potential to scavenge particularly peroxy radicals, its direct reduction of innate inflammation, and a chronic elevation of interstitial adenosine seems to be of more importance for the prevention of vascular and tissue damage than its adenosine- and prostacyclin-mediated antithrombotic effect. In its extended-release preparation with the tartaric acid nucleus, not only does it not seem to add significantly to the risk of bleeding, but seems to hold potential for protecting tissue from oxidative and metabolic stress. Copyright © 2012 S. Karger AG, Basel.