Antiphospholipid antibodies are autoantibodies that recognize phospholipid-binding proteins such as β2 glycoprotein (β2GP)-I, prothrombin or annexins. These antibodies have been associated with arterial or venous thrombotic events and pregnancy morbidity. The molecular mechanisms responsible for the pathogenetic potential of these antibodies include: resistance to activated protein C, acquired Factor XII deficiency resulting in suppression of intrinsic fibrinolytic activity, activation of endothelial cells through the nuclear factor κB pathway leading to tissue factor upregulation, adhesion molecule and cytokine expression and activation of platelets. Opposite effects, such as the potentiation of the inhibitory action of β2GPI on the activation of Factor XI, make the dynamics of the interaction of these antibodies with the coagulation system rather complex. Many of the above functions can be mediated by signaling through molecules of the tumor necrosis factor receptor family, such as CD40, which is recognized by purified anti-β2GPI antibodies.