Although patients aged ≥75 years represent nearly 40% of all those hospitalized with acute coronary syndromes, their enrollment in trials of therapeutic interventions has been relatively modest. Thus, scarce information exists to guide clinicians in decision-making and assessing projections of safety and efficacy for antiplatelet agents. The pathobiology of aging, including age-related changes in vascular repair and integrity, applies to patient management and offers a platform for investigation. Because older patients receive excess dosing of antithrombotic agents much more often than their younger counterparts do, initial steps toward optimized care include attention to indications, dosing, and duration of treatment. This review, representing a summary of information presented at the Fourth Annual Platelet Colloquium held in Washington, DC, in January 2009 and supplemented with recent clinical trial results, underscores an increasingly narrow safety index for antiplatelet agents in the elderly and the all-important balance of safety and efficacy—a dynamic continuum that remains paramount in quality of care. Considerations for future trial designs, registries, and analyses of existing data are highlighted to better guide clinicians toward the optimal management of this rapidly growing, high-risk group.