Antiplatelet therapy is the cornerstone of secondary prevention in cardiovascular disease. This review focuses on the role of antiplatelet therapy in atrial fibrillation (AF) and heart failure (HF). Aspirin has a limited role in stroke prevention among most patients with AF, being of limited efficacy and not any safer than warfarin, especially in the elderly. For HF patients with AF, cardioembolism is a major cause of stroke, and antiplatelet alone would be insufficient thromboprophylaxis. Aspirin plus clopidogrel rather than aspirin alone is preferred for those AF patients who have refused any form of oral anticoagulation. For AF patients undergoing percutaneous coronary intervention, triple antithrombotic therapy (aspirin, clopidogrel, and warfarin) is recommended for the initial period (1-6 months) based on the stent type, followed by vitamin K antagonists (VKA) and clopidogrel or, alternatively VKA and aspirin for up to 12 months. In AF patients with stable vascular disease, VKA monotherapy would suffice.