Anticoagulation has transformed the management of multiple potentially catastrophic disease states. Currently, available anticoagulation agents work on the common pathway of the coagulation cascade, inhibiting both thrombosis as well as hemostasis and increasing the risk of serious bleeding. Factor XIa inhibitors may completely change this anticoagulation landscape. Factor XIa affects the intrinsic thrombosis pathway, preserving the extrinsic and common pathways. Phase 2 data on multiple factor XIa inhibitors support a favorable safety profile for implementation, with reduced risk of bleeding being a consistent theme, for VTE prophylaxis, secondary stroke prevention in atrial fibrillation (AF), post-myocardial infarction (MI), and post-non-embolic stroke. This program explores novel factor XIa inhibitors currently under investigation and outlines anticoagulation’s exciting future.