Platelet aggregation, a process mediated by GP IIb-IIIa, is responsible for the occlusive events in thrombosis: indeed, GP IIb-IIIa antagonists are effective in blocking arterial thrombosis. Recent studies have suggested that activated platelets and platelet thrombi can contribute significantly to the initiation and progression of atherosclerosis, a chronic inflammatory disease. Platelets store inflammatory cytokines such as CD40L and RANTES, which are now known to be important in this pathologic process. CD40L appears to be particularly relevant because high levels of the circulating soluble form of CD40L, termed sCD40L, are released in response to platelet thrombosis and because elevated levels of sCD40L are a reliable predictor of cardiovascular events. sCD40L is also a ligand of GP IIb-IIIa and is involved in thrombus stabilization and platelet activation. In addition, GP IIb-IIIa antagonists unexpectedly block release of sCD40L. These observations suggest that long-term benefit of GP IIb-IIIa antagonists treatment could be due not only to the inhibition of the acute ischemic complications, but also to the inhibition of autocrine function of sCD40L, thereby interrupting the platelet CD40L/GP IIb-IIIa axis.