Venous thromboembolic disease, including deep vein thrombosis and pulmonary embolism, is a cause of significant mortality and morbidity. For several decades, anticoagulant options for the treatment and prevention of thrombosis have been limited mainly to agents such as unfractionated heparin and oral vitamin K antagonists such as warfarin. Although these therapies have proven benefits, they also have important limitations that result in their underuse in routine clinical practice. A variety of novel anticoagulants with improved pharmacologic and clinical profiles are in development, offering benefits over traditional therapies. Specifically, progress has been made in the development of small molecule Factor Xa inhibitors and thrombin inhibitors. The most advanced drugs reviewed include DPC-423, DPC- 602, razaxaban, GSKs 813893, Portolas Xa inhibitors (formerly Millennium), otamixaban, DU-176b, KFA-1982, BAY- 59-7939, DX-9065a, YM-150, LY-517717, Exanta, 3DPs thrombin inhibitors, SSR-182289, LB-30057, LB-30870, BIBR-1048 and Mercks thrombin inhibitors. With their potentially consistent and predictable pharmacological profile, oral formulation, and decreased need for coagulation monitoring, these new agents will likely increase the use and duration of anticoagulation treatment in thromboembolic disorders and reduce the burden associated with long-term management.