Clinical trials have demonstrated the usefulness of antiplatelet agents, percutaneous coronary intervention, and glycoprotein (GP) IIb/IIIa inhibitors in patients with acute coronary syndrome (ACS) based on risk stratification. Studies like RITA 3 and FRISC II have shown that an early invasive strategy in high-risk patients was associated with lower mortality over the long term compared with conservative treatment. High-risk patients with unstable angina/non-ST-elevation myocardial infarction derive particular benefit from GP IIb/IIIa inhibitors and an early invasive strategy. The TIMI risk score for patients with unstable angina/non-ST-elevation myocardial infarction provides an easily implemented tool for therapeutic decision-making. Simultaneous assessment of troponin, C-reactive protein, and brain natriuretic peptide at the time of presentation of ACS provides incremental prognostic information. Recent evidence supports the fact that thrombosis and inflammation are interrelated (platelets are involved in inflammation and, similarly, leukocytes are involved in hemostasis). The platelet, which was once viewed as a bystander in hemostasis, is now recognized as a key mediator of thrombosis as well as inflammation. Antithrombotic drugs block platelet aggregation and activation at various points in the thrombotic cascade and include aspirin, the thienopyridine clopidogrel, and its predecessor ticlopidine, intravenous GP IIb/IIIa inhibitors, which block the final common pathway of platelet activation and aggregation, unfractionated heparin and low-molecular-weight heparin, notably enoxaparin, and direct thrombin inhibitors (eg, bivalirudin). Bivalirudin has proven noninferior to heparin in patients undergoing percutaneous coronary intervention. Enoxaparin is emerging as a safer and better alternative to unfractionated heparin in invasively managed patients. Declining renal function is a major cause of excess dosing of antithrombotic agents and frequently increases the risk of bleeding in elderly patients. Class I American College of Cardiology/American Heart Association recommendations for acute (<24 hours) management of patients with high-risk non-ST-elevation ACS include the use of aspirin, beta-blockers, unfractionated heparin or low-molecular-weight heparin, or GP IIb/IIIa inhibitors for patients undergoing catheterization and revascularization and clopidogrel for patients undergoing percutaneous coronary intervention. Medical therapy should be coupled with an early invasive strategy of catheterization and revascularization within 48 hours. Predischarge initiation of secondary prevention therapies for risk factor modification may have substantial advantages for improving the long-term prognosis of patients. A large proportion of patients with ACS undergo interventional treatment, which underscores the importance of upstream initiation of antithrombotic agents. Data from CRUSADE suggests that the majority of patients are likely to benefit from aggressive upstream antithrombotic therapy. Patients with ACS who have diabetes have a higher risk for recurrent events than their nondiabetic counterparts but stand to benefit more from early aggressive therapy. Combining GP IIb/IIIa inhibition with drug-eluting stents offers the potential to optimize outcomes after revascularization in patients with diabetes. Whereas the use of drug-eluting stents has greatly reduced the risk of restenosis, patients with diabetes who have ACS and who undergo stenting remain at high risk for restenosis and are more likely to require revascularization. Increasing adherence to American College of Cardiology/American Heart Association guidelines is key to improving outcomes. The optimal management of patients with ACS continues to change as new therapies and strategies of care are developed and proven effective. The clinical challenge remains to increase physician adherence to evidence-based cardiac care for all patients.