Anticoagulation, aimed at mitigating the enlargement of obstructive thrombi in coronary arteries, is a cornerstone of treatment for patients with unstable coronary artery disease. Limitations of currently available pharmacologic agents have sustained substantial interest in discovering novel anticoagulants that may more effectively and safely dampen the activation and perpetuation of the coagulation cascade that contributes to acute coronary syndromes. Tissue factor plays a critical role in initiating the molecular events leading to thrombus formation and thus is an attractive target to inhibit blood coagulation at the most proximal level, quenching the effect of downstream amplification that occurs in the coagulation cascade. Recent studies demonstrating the safety and efficacy of inhibiting tissue factor for reducing thrombin generation in patients with coronary artery disease support the promise of this class of novel anticoagulants for the treatment of acute coronary syndromes.