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It is estimated that in the United States, each year, approximately 620,000 persons will experience an acute coronary syndrome and approximately 70% of these will have non–ST-elevation acute coronary syndrome. Cardiovascular disease still accounts for 1 of every 3 deaths in the United States, and there is an urgent need to improve the prognosis of patients presenting with acute coronary syndrome. Cardiovascular mortality and ischemic complications are common after acute coronary syndrome, and the advent of newer antithrombotic therapies has reduced ischemic complications, but at the expense of greater bleeding. The new antithrombotic agents also raise the challenge of choosing between multiple potential therapeutic combinations to minimize recurrent ischemia without a concomitant increase in bleeding, a decision that often varies according to an individual patient's relative propensity for ischemia versus hemorrhage. In this review, we will synthesize the available information to arm health care providers with the contemporary knowledge on antithrombotic therapy and individualize treatment decisions.