Antiplatelet therapy is the cornerstone of management in acute coronary syndromes (ACS) and percutaneous coronary intervention. Combination therapy with aspirin and clopidogrel reduces the risk of death, myocardial infarction, or stroke in ACS but increases the risk of major bleeding, which studies indicate is 1%-4% higher when clopidogrel is added to aspirin. Given the association between bleeding and adverse outcomes, minimizing bleeding risk is a clinical priority. This review outlines strategies to reduce both acute and chronic bleeding risk with aspirin and clopidogrel and focuses on dosing of concomitant therapies, vascular access techniques, and mitigating the bleeding risk associated with coronary artery bypass grafting surgery.