Acute coronary syndromes (ACS) refer to a spectrum of myocardial ischemic disorders characterized by atherothrombotic plaque disruption. The management of ACS presents a challenge to the cardiologist because treatment strategies continue to evolve. Thrombin plays a pivotal role in thrombus formation, converting fibrinogen to fibrin, activating platelets, and recruiting additional platelets into the platelet-rich thrombus. In addition to unfractionated heparin (UFH), newer antithrombotic agents are now available and have significantly changed contemporary clinical practice. Low-molecular-weight heparins (LMWHs) has been shown to be superior to UFH in several trials. Direct thrombin inhibitors (DTIs) have been shown to be effective in patients undergoing elective coronary interventions and are being evaluated in patients with ACS. We review two classes of antithrombotic drugs, the LMWHs and the DTIs and discuss their current roles in the management of patients with ACS.