The combination of aspirin and clopidogrel is the mainstay antiplatelet therapy for acute coronary syndromes (ACS). However, the dosing of aspirin, the dosing of clopidogrel, the timing of clopidogrel initiation as well as the duration of clopidogrel therapy remain controversial matters. Clopidogrel resistance is an emerging concept with potential clinical implications. In the era of clopidogrel and bivalirudin, the role of glycoprotein IIb/IIIa antagonists is being challenged, yet they are still indicated in a select high-risk population. Concerning anticoagulant use in ACS, newer agents, bivalirudin and fondaparinux, have improved outcomes in comparison to heparin in patients managed with an invasive or conservative strategy, respectively. Combining multiple antiplatelet agents and an anticoagulant is the standard of care for ACS.