Venous thromboembolism remains a frequent cause of vascular death. Despite advances in anticoagulant drug development, unmet needs remain, including limited treatment options for patients with severe renal impairment and the inability to fully reverse the effects of anticoagulants approved or in late-stage development. Because coagulation factor IXa plays a pivotal role in tissue factor-mediated thrombin generation, it represents an attractive target for anticoagulant development. This article discusses the rationale for factor IXa as an anticoagulant target and the potential role in venous thromboembolism prevention or management of the 2 factor IXa inhibitors that have undergone testing in phase 1 or 2 trials: TTP889, an oral, small-molecule compound, and RB006, an aptamer-based compound, the intravenous and subcutaneous formulations of which are the anticoagulant components of the REG1 and REG2 anticoagulation systems, respectively.