Platelets are important mediators of thrombosis in both healthy and diseased vessels. When platelets become activated by various soluble agonists or by adhesion to subendothelium under high shear, they release adenosine-5'-diphosphate that acts in a positive feedback mechanism on two different G-protein coupled receptors (P2Y(12), P2Y(1)) on platelets. This released adenosine-5'-diphosphate, acting through P2Y(12), is critical for sustained aggregation and stabilization of thrombi. P2Y(12) is the target of antithrombotic drugs (ticlopidine, clopidogrel), whereas the role of P2Y(1) in thrombosis remains to be fully established. Recent studies using either inhibitors of key components of signaling pathways or genetically engineered mice have contributed to our understanding of the signaling mechanisms in platelets mediated by adenosine-5'-diphosphate through the P2Y(12) receptor. Studies of patients with defective adenosine-5'-diphosphate mediated aggregation, as well as P2Y(12)-null mice, have revealed the importance of this receptor in mediating platelet activation and aggregation. Recent clinical trials using approved P2Y(12) blockers have extended the use of these drugs to additional patient populations. Recent data demonstrating the role of P2Y(12) in mediating platelet adhesion to thrombogenic surfaces (collagen, von Willebrand factor) provide further rationale as to the clinical efficacy of P2Y(12) blockers. P2Y(12) antagonists in combination with anticoagulants (thrombin inhibitors, factor Xa inhibitors) act synergistically in inhibiting thrombus formation (similar to aspirin) ex vivo. These findings suggest the potential for combination therapies (P2Y(12) antagonists with inhibitors of GPIIb-IIIa, thrombin or Factor Xa, etc.) to provide additional clinical benefit to patients with various cardiovascular diseases, especially those who may be aspirin-resistant.