Studies have demonstrated the efficacy and safety of unfractionated heparin and low-molecular-weight heparin in the management of patients with acute coronary syndrome. However, a common limitation of unfractionated heparin and low-molecular-weight heparin is that neither can neutralize clot-bound thrombin. To overcome this limitation of the broad heparin-based anticoagulants, novel anticoagulants targeted for both the free and clot-bound forms of thrombin (direct thrombin inhibitors), or other individual components of the coagulation cascade (eg, direct and indirect factor Xa inhibitors), were developed. These targeted anticoagulation agents showed promising results in preclinical testing and have been evaluated in large-scale clinical acute coronary syndrome trials. This review discusses the disconnect between the excellent preclinical findings obtained with these novel, targeted agents and the efficacy and safety data observed in patients with acute coronary syndrome, compared with the broader-range heparin-based anticoagulants.