The endothelium is the principal anti‐thrombotic mechanism, providing a non wettable surface and generating potent vasodilators (nitric oxide and prostacyclin) and clotting inhibitors [thrombomodulin and tissue factor pathway inhibitor (TFPI)]. When the integrity of the endothelium is breached, vasoconstriction occurs through neural and chemical (endothelin, thromboxane) mechanisms, and platelet adhesion is facilitated (von Willebrand factor). Activation of platelets accompanied by microparticle formation provides a thrombogenic surface for subsequent coagulation reactions. The initial generation of small amounts of thrombin greatly amplifies subsequent clotting factor activation and results in substantial thrombin formation. Thrombin activates an inhibitor of fibrinolysis [thrombin activatable fibrinolysis inhibitor (TAFI)] which prevents the binding of plasminogen to fibrin. Mechanisms to limit clot formation include inhibition of the tissue factor–factor VIIa complex by TFPI, inhibition of activated factors V and VIII by activated protein C, and binding of thrombin by thrombomodulin, heparin cofactor II, and anti‐thrombin. Clot dissolution is promoted by plasminogen activators (tissue plasminogen activator and urokinase) and by plasminogen.