Factor Xa is the serine protease that activates prothrombin to yield thrombin. Inhibitors of factor Xa play a crucial role in curtailing thrombin generation. Two key factor Xa inhibitors that are found in blood are antithrombin III and tissue factor pathway inhibitor. Inhibition of factor Xa is a mechanism that is also exploited by certain hematophagous animals to facilitate feeding. Evaluation of tick anticoagulant peptide (TAP) and leech-derived antistasin (ATS) using animal models of thrombotic disorders has confirmed that specific blockade of factor Xa activity is an effective antithrombotic strategy. Several laboratories are currently pursuing low-molecular weight synthetic factor Xa inhibitors for use as anticoagulants in the treatment and/or prevention of thrombosis.