Antiplatelet therapy is the cornerstone for both primary and secondary prevention therapies for ischemic events resulting from coronary atherosclerotic disease. Dual antiplatelet therapy (aspirin plus a thienopyridine, usually clopidogrel) has assumed a central role in the treatment of acute coronary syndromes and after coronary stent deployment. In addition to antiplatelet therapy, anticoagulant therapy might be indicated for stroke prevention in a variety of conditions that include atrial fibrillation, profound left ventricular dysfunction, and after mechanical prosthetic heart valve replacement. For this reason, the use of triple antithrombotic therapy (a dual antiplatelet regimen plus warfarin) is expected to become more prominent, given an aging patient population. But although triple therapy can prevent both thromboembolism and stent thrombosis, it is also associated with significant bleeding hazards. Furthermore, when bleeding events do occur, the challenge of balancing the risk of stent thrombosis or stroke and the need for hemostasis requires considerable expertise. It is both prudent and timely to review treatment strategies that employ combinations of antiplatelet and anticoagulant therapies as well as strategies aimed at reducing bleeding risk in patients treated with these therapies.